Multi-Center, Randomized, Placebo-Controlled, Double Blind ......ONET (Oriental Neurosurgical Evidence-based Team) 1 148 1. Background 149 Chronic subdural hematoma (CSDH) is a common

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Multi-Center, Randomized, 5

Placebo-Controlled, Double Blind Study of 6

the Atorvastatin: Effect on Patients With 7

chronic subdural hematoma 8

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Version:1.0 18

Date:18 th,Oct,2013 19

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Organization Committee： 21

ONET (Oriental Neurosurgical Evidence-based Team) 22

Neurosurgery department 23

Tianjin medical university General hospital 24

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Downloaded From: https://jamanetwork.com/ by a Non-Human Traffic (NHT) User on 02/16/2020

Clinical trial of Atorvastatin therapy on CSDH Serial Number：BHR-I00-301

Oriental Neurosurgical Evidence-based Team（ONET）

Clinical Sites Sponsoring in the Study 29

Beijing Tiannan Hospital affiliated to Capital Medical University 30

Peking Union Medical College Hospital 31

Chinese PLA General Hospital 32

Huashan Hospital of Fudan University 33

Shanghai Changzheng Hospital 34

West China Hospital, SCU 35

Xiangya Hospital Central South University 36

The First Affiliated hospital of Harbin Medical University 37

Qilu Hospital of Shandong University 38

Southwest Hospital 39

Xijing Hospital 40

The Second Affiliated Hospital of Zhejiang University School of Medicine 41

Prince of Wales Hospital 42

Clinical Sites Participating in the Study 43

Tangdu Hospital 44

Tongji Medical College of HUST 45

Jangsu Province Hospital 46

Nanfang Hospital 47

The First Affiliated Hospital of Fujian Medical University 48

The Second Affiliated Hospital of Hebei Medical University 49

Anhui Province Hospital 50

The First Affiliated Hospital of Zhengzhou University 51

The First Affiliated Hospital of Shanxi Medical University 52

General Hospital of Ningxia Medical University 53

The Affiliated Hospital of Xuzhou Medical University 54

Hainan General Hospital 55

Inner Mongolia People’s Hospital 56

Ordos Cental Hospital 57

Cangzhou Cental Hospital 58

Linyi People’s Hospital 59




The PLA 117 Hospital 60 Statistical Analysis 61 Beijing Stemexcel Technology Co.,Ltd 62 63

Contract Research Organization 64

Beijing Stemexcel Technology Co.,Ltd 65

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Contents 70

Protocol abstract ........................................................................................................................... - 5 - 71 1. Background ............................................................................................................................... 1 72 2. Objective of the study ............................................................................................................... 8 73 3. Study design .............................................................................................................................. 8 74

3.1 Overall design ........................................................................................................... 8 75 3.2 Case number and grouping method ........................................................................... 8 76 3.3 Blinding and randomization ...................................................................................... 8 77

4. Study population ....................................................................................................................... 9 78 4.1 Inclusion Criteria ....................................................................................................... 9 79 4.2 Exclusion Criteria .................................................................................................... 10 80 4.3 Group alteration ...................................................................................................... 10 81 4.4 Abortion Criteria ..................................................................................................... 11 82 4.5 Withdrawal .............................................................................................................. 11 83 4.6 Deletion criteria ....................................................................................................... 11 84

5. Study procedure ...................................................................................................................... 12 85 5.1 Study Flow chart ..................................................................................................... 12 86 5.2 Screening assessment .............................................................................................. 14 87 5.3 Included subjects ..................................................................................................... 15 88

6. Treatment protocol .................................................................................................................. 16 89 6.1 The name of the drug and specification .................................................................. 16 90 6.2 Drug packaging ....................................................................................................... 16 91 6.3 Treatment ................................................................................................................ 16 92 6.4 Drug distribution ..................................................................................................... 18 93 6.5 Drug management ................................................................................................... 18 94 6.6 Concomitant medications and treatment ................................................................. 19 95 6.7 Drugs prohibited during treatment .......................................................................... 19 96

7. Evaluation Parameters ............................................................................................................. 19 97 7.1 Safety Parameters .................................................................................................... 19 98 7.1.1Complications ................................................................................................................. 19 99 7.2 Efficacy Parameters ................................................................................................ 20 100

7.2.1 Parameters of the curative effect ..................................................................... 20 101 7.2.2 Quality control and Quality assurance in effective parameters ....................... 21 102

8. Termination and Withdrawal of Subjects ................................................................................ 21 103 8.1 The terminal point of this trial ................................................................................. 21 104 8.2 Withdrawal of Subjects ........................................................................................... 21 105

9. Adverse Event and Serious Adverse Event ............................................................................. 22 106 9.1 Adverse Event ......................................................................................................... 22 107 9.2 Abnormalities in the clinical laboratory test ........................................................... 22 108 9.3 Serious Adverse Event（SAE） ............................................................................. 23 109

10. Data management .................................................................................................................... 23 110 10.1 Electronic Data Management .................................................................................. 23 111 10.2 Make the plan of data manage ................................................................................. 25 112




11. Statistical Analysis .................................................................................................................. 26 113 11.1 Determination of sample size .................................................................................. 26 114 11.2 Analysis of the data set ........................................................................................... 27 115 11.3 Statistical Methods .................................................................................................. 27 116

11.3.1 Subject Distribution Analyses ......................................................................... 27 117 11.3.2 Demographic and Baseline Comparability ...................................................... 28 118 11.3.3 Efficacy Analyses ............................................................................................ 28 119 11.3.4 Safety Analysis ................................................................................................ 29 120

11.4 Statistical software and general requirements ......................................................... 29 121 11.5 Interim Analysis ...................................................................................................... 29 122

12. Trial Management ................................................................................................................... 30 123 12.1 Ethics ....................................................................................................................... 30 124 12.2 Informed consent and data protection agreement .................................................... 30 125 12.3 Withdraw from clinical study .................................................................................. 31 126 12.4 Subjects Privacy ...................................................................................................... 31 127 12.5 Modification of the clinical trial protocol ............................................................... 31 128 12.6 CRF ......................................................................................................................... 32 129 12.7 Original records certification .................................................................................. 32 130 12.8 Publication .............................................................................................................. 32 131 12.9 Documents on file ................................................................................................... 32 132 12.10 Quality control and assurance ................................................................................. 33 133 12.11 Clinical research controller ..................................................................................... 33 134 12.12 Research schedule ................................................................................................... 33 135 12.13 Clinical research institutions ................................................................................... 34 136

13. Appendix ................................................................................................................................. 36 137 13.1 Adverse Event Degree ............................................................................................. 36 138 13.2 Relativity Between Adverse Events and the Drug Estimation ................................ 37 139 13.3 MGS-GCS ............................................................................................................... 38 140 13.4 GCS ......................................................................................................................... 39 141 13.5 ADL-BI ................................................................................................................... 40 142 13.6 GOS (Glasgow Outcome Score) ............................................................................. 43 143

14. Signature of each organization involved in the clinical trial ................................................... 44 144 15. References ............................................................................................................................... 46 145

146




Protocol abstract 147

Drug Atorvastatin

Title Multi-Center, Randomized, Placebo-Controlled, Double Blind Study of

the Atorvastatin: Effect on Patients with Chronic Subdural Hematoma

Objective To evaluate the clinic efficacy and safety of oral administration of

Atorvastatin on patients with chronic subdural hematoma (CSDH).

Study design Multi-center, randomized, placebo parallel controlled, double-blind

study

Subjects Patients with chronic subdural hematoma (CSDH)

Sample size 200 cases, of which 100 in an Atorvastatin-treated group while 100 in a

control group.

Inclusion criteria

1.Age ≥18 and ＜90 years old, both gender;

2.CT scan reveals supratentorial, unilateral or bilateral chronic

subdural hematoma (MRI scan is warranted if diagnosis is difficult);

3.Markwalder’s Grading Scale and Glasgow Coma Scale (MGS-GCS)

< Grade 3;

4.Attending physician makes a judgment that cerebral hernia would

not occur and surgical operation might not be performed in a short time.

Conservative treatment is adopted;

5.Patients have never undergo surgery on the hematoma;

6.Patient fully understood the nature of the study, and voluntarily

participates and signs informed consent.

Exclusion criteria

1.Allergic to the statin or its ingredients;

2.Cerebral herniation might occur at any time;

3.Hematoma leads to herniation and warrants surgical operation;

4.Hematoma caused by tumors, blood and other known comorbidities;

5.Abnormal liver function;

6.Uncontrolled hepatitis and other liver diseases, as well as suffering

from other disease may interfere the study;

7.Patients have been on oral Statin for a long time;

8.Patients have been on oral Steroids for a long time;




9.Participate in clinical trials in the past four weeks;

10.Pregnant or breastfeeding;

11.Failure of completing the trial by poor compliance;

12.For any reason, the researchers believe that the case is not suitable

for inclusion.

Elimination and

withdrawal criteria1.

1. Misdiagnosis;

2. Never medication;

3. Lack of evaluable records after medication;

4. The use of prohibited drugs during the trial.

The reasons for deletion should be recorded and CRF should also

be retained for future review. Simultaneously no efficacy statistical

analysis will be made, but the patient received at least one treatment

with safety record, safety analysis should be conducted accordingly.

Therapeutic scheme

1. Besides routine treatments, the patients in atorvastatin treatment

groups take atorvastatin tablets orally, with starting dose of 20 mg

(every evening) for 8 weeks . The patients in control group received a

placebo with the same appearance tablets.

2. The treatment regimen initiates right after the inclusion.

3. If MGS - GCS deteriorated or the volume of hematoma increased

during the conservative treatment, the patients will be undergo surgical

operation. After operation, the treatment regimen resume to complete

the full clinical trial (8 weeks).

4. After 8 weeks treatment, hematoma was assessed, follow-up

treatment continued according to processes.

5. Non-enhanced head CT was performed before the treatment, at the

4th week and 8th week during treatment (at the end), at the 12th week

and 24th week during the follow-up. MGS – GCS, GOS and ADL - BI

scores were evaluated during follow-up as well.

Group alteration

1. Surgical operation: During conservative treatment, if patients’

MGS-GCS grades drop, the size of hematoma expands, and might

develop cerebral herniation, they must be changed to surgical treatment

group.




2. After group alteration, continue on the treatment regimen until the

end of the trial (8 weeks).

Observation period

Duration of treatment: oral administration of atorvastatin or placebo for

8 weeks;

Duration of follow-up: 24 weeks after treatment ending.

Major curative effect

indices

The change of hematoma volume（non-enhanced CT scan）at 8th week.

Secondary curative

effect indices

1. The change of hematoma volume（non-enhanced CT scan）at 4th

week during treatment and 12th, 24th week during follow-up;

2. MGS – GCS, GOS and ADL - BI scores

3. Symptoms and signs;

4. Blood test and coagulation indicators.

Security evaluation

Adverse effects, severe adverse effects (postoperative complications:

fever, infection; non-postoperative neuromuscular changes, liver

function changes, encephalic hematoma, cerebral edema, cerebral

infarction, epilepsy, and laboratory tests).

Statistical analysis

Data will be analyzed by two-sided analysis; p value less than 0.05 will

be considered statistical significance.

SAS 9.3 software will be adopted for statistical analysis.




1. Background 148

Chronic subdural hematoma (CSDH) is a common type of encephalic hematoma 149

in neurosurgery. More than half of CSDH patients have a history of head injury, and 150

show clinical symptoms and signs after 21 days (more than 3 weeks), which can be 151

confirmed by imaging. The incidence of CSDH was reportedly 1-13.1 in every 152

100,000 people [1,2]. The formation of subdural haematoma can be explained by 153

many hypotheses, but none of them is recognized. 154

Surgical therapy has long been the major therapy of CSDH. This is because 155

clinical observations show that, different from subacute subdural hematoma (SSDH), 156

of which the majority can be absorbed conservatively. CSDH can seldom be 157

spontaneously absorbed, and no literature ever reports in detail the rate of 158

spontaneous absorption in CSDH patients. CSDH patients are cured mainly by 159

burr-hole drainage, and partially by endoscopic treatment. Whatever surgery is 160

used, its reoccurence rate was up to 20% [3]. Besides, most CSDH patients are the 161

elderly, and cases of death were yet reported postoperativly due to postoperative 162

infection, pneumonia, tensile pneumonedema, or cerebral cotusion and laceration. In 163

clinic, some elderly patients with brain atrophy did not show evident symptoms or 164

intracranial hypertension, so they may receive conservative treatment and close 165

imaging observations, complemented by drugs. The conservative drug treatment 166

methods include pure repose care, intracranial pressure reduction by mannitol 167

dehydration, and glucocorticoid treatment. Reportedly, oral administration of 168

Dexamethasone for therapy of partial CSDH showed favorable curative effects; 169

therefore, partial CSDH can be cured by non-surgical methods [4-7].However, due to 170

obesity, gastrointestinal damage and other steroid-related complications, the therapy 171

of oral dexamethas has not been promoted. 172

Epidemiological studies suggest that craniocerebral trauma is the major cause of 173

CSDH, but hematoma was discovered in some cases with history of mild head 174




trauma or even without history of trauma, especially in elderly patients who 175

developed coagulation disorder or received anti-coagulation drugs[8]. Recent 176

long-term follow-up on senile CSDH shows that even 1 year after normlized 177

treatment, CSDH still had a high mortality of 32%, and was concluded as not a 178

benign disease [9, 10]. With the rise of aging rate in China, the number of elderly 179

CSDH patients, or of patients who received stent therapy, heart bypass or 180

cerebrovascular bypass due to heart or cerebrovascular diseases is increasing; plus 181

wide utilization of anticoagulants, and increasing cases of intractable or recurrent 182

CSDH, this disease becomes another puzzle in neurosurgery. In view of this , 183

developing more secure and reliable new therapies for this disease is still an 184

important research area. 185

Little progress has been made in the pathogenesis of CSDH, but according to 186

our primary achievements and previous reports, we believe that angiogenic 187

dysfunction of hematoma film and inflammatory response within the hematoma are 188

the key reasons for hematoma formation. There are 4 reasons: 1. It was confirmed 189

that CSDH hematoma cavity contains high level of erythrocyte, which only 190

originates from continuously produced blood leak in vascular envelope, mainly 191

because the blood vessels in vascular envelope are immature. 2. Reportedly CSDH 192

patients contain high level VEGF in their hematoma fluid and serum (average VEGF 193

level in hematoma fluid is 28 times higher than serum) [11]; VEGF will promote the 194

formation of new vessels, and repress their maturation [12], which is consistent with 195

our result that CSDH hematoma envelope contains numerous immature and 196

abnormal vessels. 3. Recent clinical research shows that, CSDH patients contain 197

higher levels of various proinflammatory and anti-inflammatory factors in hematoma 198

cavity than in peripheral blood, and inflammation degree is related to hematoma 199

types and prognosis, and will affect vascular formation and vascular permeability in 200

hematoma envelope. Some clinical applications of Dexamethasone to inhibit and 201

treat partial CSDH were proved effective [13-15]. 4. Our previous studies confirmed 202

that artificial rats subdural hematoma model in early newly hematoma envelope, new 203

blood vessels are abnormally shaped or defective, and will lead to rapid formation of 204




hematoma; while blood vessels in late hematoma envelope are more mature and 205

denser, so hematoma shrinks faster [16]. 206

Statins, inhibitors of hydroxy-methylglutaryl-CoA (HMG-CoA) reductase, are 207

widely used to reduce blood fat level, and to promote vascular formation after nerve 208

damage. Our early experiments confirmed that statins could promote mobilization of 209

endothelial progenitor cells (EPCs) in blood circulation, and maintain EPCs at high 210

level for more than 14 days. Meanwhile, Atorvastatin was confirmed to significantly 211

inhibit VEGFs and reduce inflammatory reaction and relevant factors [17,18]. 212

Reportedly, statins could also promote high expressions of Notch1/Jagged1 signals, 213

which are key signals in the VEGF-regulated formation and maturation of blood 214

vessels. Also we first found that over 65% of CSDH patients have lower EPC levels 215

in blood circulation than the control group. Statins can obviously promote the 216

mobilization of EPCs in blood circulation, as well as the formation and maturation of 217

functional blood vessels [19]. The early basic experiments in this program confirmed 218

that, in comparison with the control group, small-dose (0.5mg/kg/d) Atorvastatins 219

could promote the absorption of subcutaneous hematoma clots in mice (Fig. 1-1,1-2), 220

while in the large-dose group (5mg/kg/d), absorption of hematoma was prolonged. In 221

the rat subdural haematoma model, small dose (1mg/kg/d) of Atorvastatin could 222

obviously improve EPC level in peripheral blood, and promote the maturity of new 223

blood vessels in local hematoma envelope, the normalization of local high 224

inflammation, and the absorption of hematoma (Fig. 2). Some foreign researchers 225

held that large dose of Atorvastatin would cause blooding, while small dose would 226

promote formation of vessels [19, 20]. Literatures, this animal study, and our primary 227

clinical evidence together show that 20 mg of Atorvastatin might be a suitable dose 228

to promote the formation of new blood vessels and functional vessels. Of course, 229

whether this deduction is right should be confirmed by further studies. However, 230

when there are no efficient and safe medication treatments for CSDH at the moment, 231

our successful cases of therapeutic effects show that, we should better confirm the 232

therapeutic effect of Atorvastin at this dose on CSDH, and prove the safety after 233

expanding the number of cases. 234




235 Fig. 1-1 Days needed for complete absorption of subcutaneous hematoma in different 236

groups of mice. 237 238

239

Fig. 1- 2 Trends for absorption of subcutaneous hematoma in different groups of mice. 240

241 Fig. 2 The absorption of subdural hematoma in the control group, large and small dose 242

atorvastatin group in rats. Figure A-C represent respectively, blank control group, low-dose 243 group, the high-dose group 2 days. Long arrow represents hematoma inner and outer 244 membrane, and short white arrows represent hematoma, short black arrow on behalf of 245 the cerebral cortex. FIG. D-F represent respectively blank control group, low-dose group, 246




the high-dose group 7 days. 247

Based on the above theories and experiments, we selected a group of 248

trauma-induced CSDH patients (13 cases) for studying the curative effects of oral 249

administration of Atorvastatin. The results surprisingly show that after 3-4 weeks, 250

100% of patients showed obviously smaller hematoma; after 1 month, hematoma 251

completely disappeared in more than 90% of patients, surgery was also avoided in 252

all patients ; After the longest follow-up of 3 years, no recurrence or other relevant 253

side effects were observed (typical cases showed in Fig. 3). Recently a study of total 254

23 cases from three hospitals treated with, atorvastatin for chronic subdural 255

hematoma confirmed that atorvastatin can effectively promote the hematoma 256

absorption, the results were published in 2014, Journal of the Neurological 257

Sciences[21]. 258

Selection criteria of the 13 cases: 259

1. Patients were aged 18 or over. 260

2. CT or MRI imaging implies subdural haematoma, which appeared more than 261

3 weeks after the appearance of nerve symptoms and signs. 262

3. Markwalder’s Grading Scale and Glasgow Coma Scale (MGS-GCS) < 263

Grade 3; 264

4. All patients with liver dysfunctions were excluded by liver and renal 265

examination. 266

Therapy of the 13 cases: 267

1．No patient was in hospital. 268

2． Patients orally took 20 mg/night of Atorvastatin for 1 month, and received 269

examinations on nerve symptoms and liver function, and head CT plain scan 270

upon the follows-up at month 1, month 3, and month 6. 271

Since CSDH occurs highly in the elderly, and since all treatments are not ideal, 272

the therapeutic method we discovered is simple, rapid, safe and economic. Also due 273

to wide application of statins, especially Atorvastatin which is the safest and shows 274

significantly fewer side effects than other statins, we think Atorvastatin is very 275

suitable for treatment of CSDH in elder patients. In addition, after literature search, 276




we found no report of this treatment in China and overseas. This treatment can 277

greatly save treatment costs and compensations, and alleviate the patients' fear of 278

cranial surgery. It has enormous social benefits, so it should be confirmed and 279

promoted. 280

281 Fig. 3-1. Typical case 1: female, aged 79, with 3 months of definite trauma, right 282

temporoparietal CSDH. After one and a half month of oral administration of atorvastatin 283 at 20 mg /day, hematoma was nearly absorbed. MRI performance at 4 weeks after oral 284 administration of atorvastatin shows the hematoma disappeared. 285

286 Fig. 3-2. Typical case 2: female, aged 79; he could not walk stably half year after slight 287

head trauma, with dizziness for 1 month.MRI scan revealed left lateral subdural hematoma. 288 She received therapy of Atorvastatin, and 1 weeks later, the symptoms were obviously 289 alleviated; CT reexamination 1 month later showed hematoma was apparently reduced. 290 Images at month 3 revealed the hematoma almost disappeared. 291

292




293 Fig. 3-3. Representative case 3: Male, 75 y/o, transient unconsciousness for two hours 294

after head fall injury, CT scans shows frontal parenchymal laceration and intracranial 295 hematoma (less than 10 ml). He was on conservative treatment and discharged 1 month 296 later. He complained again with unsteady gait and dizziness 6 month after discharge. CT 297 scan on admission shows that left subdural hematoma. This patient was on atorvastatin 298 treatment. His symptoms were relieved. 2 weeks later. CT scans show the hematoma 299 decreased by 3 months and disappeared by 6 months. 300

301 Fig. 3-4. Representative case 4: male, 83 y/o, presented with dizziness and unsteady 302

gait for 15 days on admission. Head CT scan show left subdural hematoma. After 303 atorvastatin treatment, the symptoms were relieved by 2 weeks. CT scan revealed the 304 hematoma almost disappears on 3 month later. 305

306

307

308




2. Objective of the study 309

To evaluate the therapeutic effects and safety of atorvastatin on CSDH. 310

3. Study design 311

3.1 Overall design 312

This project was a multicenter, randomized, double blind, parallel-group trial 313

designed study, with the purpose of evaluating the efficacy and safety of atorvastatin 314

treatment on CSDH. 315

3.2 Case number and grouping method 316

Estimated by statistical analysis, the expected patients are 200 patients. Eligible 317

patients will be randomly to receive atorvastatin (n=100) or placebo (n=100). 14 318

centers were chosen for study trial. DAS for IWRS will be used for random number 319

allocation and drug distribution, each center competes to recruit subjects. 320

3.3 Blinding and randomization 321

1. Allocation concealment and blind codes preservation 322

DAS 2.0 software package was adopted to produce random numbers according 323

to 1:1 ratio of experimental group and control group by biostatistician independent 324

of the study data management and statistical analysis. The selected block length and 325

random initial seed parameters were sealed in the envelopes as blind codes. Then the 326

sealed envelopes were handed over to sponsor, including random coding and 327

grouping information, ,bilnd codes were archived respectively. in sponsor and PI. 328

The statistician and personnel irrelevant to the test from sponsor participate in 329

the drug allocation package. According to the drug packaging, put the package 330




number and drug verification code on the tag. The trial adopts IWRS to allocate 331

drugs, so the random number of subject is unique. The random number and package 332

number could be different, but the corresponding therapy is the same. The process of 333

drug blinding is noted as blind record. The record should be signed by relevant 334

personnel, and preserved as document. 335

After the blinding, the drug package number and verification code should be 336

imported into IWRS in order to apply random number and allocate drug. 337

2. emergency envelopes 338

A set of emergency envelopes containing the treatment assigned for each 339

subject were provided to the Investigator. Emergency envelopes for the emergency 340

breaking blind are strictly authorized to the leader of each center. Only the leader 341

investigators can open the electronic envelope, and the track of opening will preserve 342

the signature of opener and the date as well as unblinding reason. 343

3. emergency unblinding 344

In case of emergency, the researchers consider observing the treatment of 345

subjects is advantageous to take care of adverse events, the unblinding can be 346

operated and signed by investigators, and the reason, data, location should be noted. 347

Within 24 hours after unblinding, notification should be made for lead units and 348

CRA and statistical personnel as well as explain the reasons for breaking the blind. 349

The unblinding case is treated as dropout, and the information should be kept intact. 350

4. Study population 351

CSDH patients from Neurology and Neurosurgery department, without 352

surgical treatment. 353

4.1 Inclusion Criteria 354

1. Age ≥18 and ＜90 years old, both gender; 355

2. CT scan reveals supratentorial, unilateral or bilateral chronic subdural hematoma 356




(MRI scan is warranted if diagnosis is difficult); 357

3. Markwalder’s Grading Scale and Glasgow Coma Scale (MGS-GCS) < Grade 3; 358

4. Attending physician makes a judgment that cerebral hernia would not occur and 359

surgical operation might not be performed in a short time. Conservative treatment is 360

adopted; 361

5. Patients have never undergone surgery on the hematoma; 362

6. Patient fully understood the nature of the study, and voluntarily participates and 363

signs informed consent. 364

4.2 Exclusion Criteria 365

1. Allergic to the statin or its ingredients; 366

2. Cerebral herniation might occur at any time; 367

3. Hematoma leads to herniation and warrants surgical operation; 368

4. Hematoma caused by tumors, blood and other known comorbidities; 369

5. Abnormal liver function; 370

6. Uncontrolled hepatitis and other liver diseases, as well as suffering from other 371

disease may interfere the study; 372

7. Patients have been on oral Statin for a long time; 373

8. Patients have been on oral Steroids for a long time; 374

9. Participate in clinical trials in the past four weeks; 375

10. Pregnant or breastfeeding; 376

11. Failure of completing the trial by poor compliance; 377

12. For any reason, the researchers believe that the case is not suitable for inclusion. 378

4.3 Group alteration 379

Surgical operation: During conservative treatment, if patients’ MGS-GCS 380

grades drop, the size of hematoma expand, and might develop cerebral herniation, 381

they must be changed to surgical treatment group. 382

After group alteration, continue on the treatment regimen until the end of the 383




trial (8 weeks). CRF has to be filled promptly. The detailed operation must be 384

faithfully recorded. The post-op follow-ups continued according to the protocol. 385

4.4 Abortion Criteria 386

Study abortion is referred to study is not terminated according to the protocol. 387

This is aiming to protect subject’s right, to guarantee medical safety and quality of 388

research, and to avoid unnecessary patient health as well as economic losses. 389

(1) Serious safety issues occurred during the research. 390

(2) The applicant requested abortion. 391

4.5 Withdrawal 392

The patient could not complete the trial for the following reason is considered as 393

withdrawal: 394

(1) Subject decides to withdraw form study (conscious poor efficacy, side effects); 395

(2) Lost to follow-up 396

(3)The investigators can request the subject to withdraw the study from the patient 397

perspective (poor compliance; serious complications; serious adverse events); 398

(4) Medication compliance is out of the 80%-120% range; 399

(5) Breaking of blindness and emergency unblinding; 400

The reasons for withdrawal should be recorded in detail and the last primary 401

efficacy results are carried over as the final results for statistical analysis, also the 402

CRF should be retained for future review. 403

4.6 Deletion criteria 404

(1) Misdiagnosis; 405

(2) Never medication; 406

(3)Lack of evaluable records after medication; 407

(4)The use of prohibited drugs during the trial 408

The reasons for deletion should be recorded and CRF should also be retained for 409

future review. Simultaneously no efficacy statistical analysis will be made, but the 410




patient received at least one treatment with safety record, safety analysis should be 411

conducted accordingly. 412

413

5. Study procedure 414

In all the clinical sites, researchers initiate the study according to enrolled order 415

only after verification of inclusion/exclusion criteria and collection of the informed 416

consents. 417

5.1 Study Flow chart 418

Patients admitted to hospital → patients were allocated based on imaging and 419

neurosurgical clinical diagnosis → Signing the related consent forms →Screening 420

assessment before treatment and randomization→ double-blind treatment → clinical 421

neurological signs and symptoms are evaluated at 1-7days, 2 , 3 , 4, 8 , 12 and 24 422

weeks after treatment. Head CT scans are performed on week 4 and 8. During oral 423

medication treatment，the study will be terminated once the disease progressed, 424

and convert to change group treatment (patients will still taken the trial drugs until 425

the end of 8-week treatment) →After 8 weeks treatment, hematoma was assessed for 426

CT, follow-up observation will be continued according to processes.Including GOS, 427

ADL, Head CT scan at 12 weeks and 24 weeks → compared with pre-treatment. 428




429

Items Base -

line

Day

1

Day

2-6

Day

7

week

2

±1

day

week

3

±1

day

week

4

±1

day

week 8

±3 day

（end of

treatment）

week

12

±3

day4

week

24

±7

day4

Sign info。 consent √

Collecting history

Inclusion/exclusion √

Filling general info √

History taken √

Combined drug1 √ √ √ √ √ √ √ √ √

Physical Exam √ √ √ √ √ √ √ √

Convert to surgery √ √ √ √ √ √ √ √ √

Efficiency observation

Neuro - symptoms3 √ √ √ √3 √3 √3 √ √ √ √

Hematoma Vol。

CT3 √ √ √ √ √

MGS-GCS3 √ √ √ √ √ √

ADL-BI √ √ √ √ √ √

GOS √ √ √ √

CBC √ √ √ √ √

Coagulation √ √ √ √ √

Safety observation

Urinalysis √ √ √

LF、RF √ √ √ √ √

Electrolytes √ √ √ √ √




Boold lipid √ √ √ √ √

Pregnancy test √

Vital signs √ √ √ √ √ √ √ √ √ √

ECG √ √ √ √

Adverse effects √ √ √ √ √ √ √ √ √

Others

Allocate random

NO √

Drug provide √ √ √ √ √

Drug recover2 √ √ √ √ √

Note: 430

1. Concomitant medication records need to be sustained to 8 weeks until termination 431

2. Remaining drugs need to be recovered; 432

3. If neurological signs increase, symptom becomes worse, MGS-GCS scores drop, 433

prompt CT scan is warranted. As long as hematoma increase, change group. 434

4. At week 12 and 24, Hematoma CT should be done ,other Laboratory examinations 435

will be selected when needed. 436

5.2 Screening assessment 437

Researcher should clearly record each subject sufficed with inclusion or 438

exclusion criteria or not on the spreadsheet. Screening assessment and inclusion 439

should not exceed 72 hrs. The following should be performed during screening: 440

1. Signing informed consent (before screening). 441

2. Demographic data: including nationality, date of birth, gender, et al. 442

3. History collection: 443

History of present illness: diagnosis, symptoms, the site of the lesion, ASA 444

classification, etc. 445

Allergies, family history, past history, et al. 446

4. Physical examination, checking vital signs; height, weight, body temperature, 447




breathing, heart rate, blood pressure; 448

5. Evaluation of neurological signs and symptoms: MGS-GCS score, ADL-BI, GOS; 449

headache can be subjective grading, limb muscle strength grade, pathological signs 450

should be truthfully recorded. 451

6. Physical and chemical examination: head CT, MRI, ECG is enrolled within the 452

inspection results. 453

● head CT: hematoma size calculated by software; 454

●head MRI: If diagnosis is difficult, head MRI is warranted 455

●Complete Blood Counts: red blood cells, hemoglobin, white blood cell and 456

platelet count; 457

● Biochemical analysis: Na, K, Cl, total Cholesterol, triglyceride, ALT, AST, 458

GGT, total bilirubin, BUN, Crea. 459

●Coagulation: prothrombin time (PT), international normalized ratio (INR), 460

activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), 461

D-dimer; 462

●Urinalysis: pH, SB, Pr, Glu, RBC 463

● electrocardiogram; 464

7. After enrollment, randomization and drug distribution are conducted by landing 465

DAS for IWRS system . 466

5.3 Included subjects 467

1. Routine blood test, routine urine test, coagulation and Biochemical analysis were 468

rechecked before enrolling into group, as well as neurological assessment. 469

2. At week 1, 4, 8, 12 and 24, routinely check blood test, urine test, coagulation, 470

Biochemical analysis and re-evaluate neurological function. 471

3. CT scans are performed at week 4, 8, 12 and 24 to measure hematoma volume and 472

neurological function. MGS-GCS, ADL-BI and GOS were scoring at week 4, 8, 12 473

and 24. 474

Note:CT scans should be performed at week 12 and 24,Other Laboratory examinations 475




should be selected when needed. 476

6. Treatment protocol 477

6.1 The name of the drug and specification 478

The drugs are provided by Pfizer, while placebo (pharmaceutically acceptable 479

adjuvants of dextrin and starch etc., with drug inspection report) is provided by 480

manufacturer with GMP certificated by the State Food and Drug Administration. 481

6.2 Drug packaging 482

Drugs are packed according to the subject, both packages of test drug and 483

placebo were labeled. label information includes drug packaging number, 484

verification code, drug name, dosage, specifications, storage, batch number, period 485

of use, production company and the words "For clinical study using", etc. Qualified 486

subjects are enrolled in test group or control group randomly through Central 487

Randomization System. 488

6.3 Treatment 489

The patients undergo the conventional standard treatment of chronic subdural 490

hematoma. In addition, double-blind, randomized of two groups were compared: 491

Groups of Atorvastatin treatment: oral administration atorvastatin tablets, 492

with a starting dose of 20 mg (once every evening) for 8 weeks, the total course is 493

eight weeks. 494

Groups of placebo treatmen: with the same shape of atorvastatin as the 495

corresponding dose, and the same time of oral atorvastatin tablets. 496

Experimental: Pfizer,Inc.. 497

Placebo: ShanDong ARURA Pharmaceutical Research & Development CO., 498

LTD. 499




Follow-up treatment (After eight weeks of medication treatment): 500

After eight weeks of medication treatment, the volume change of hematoma is 501

evaluated by CT（increased and preserved hematoma volume could possibly be observed 502

both in placebo group and atorvastatin treatment group）: 503

1. If the hematoma disappeared, or is very small, over two attending physicians or 504

above determine whether it can be stopped subdural hematoma related treatment, patients 505

were followed up for only a simple observation until the end of the 24 weeks of follow-up. 506

2. If the hematoma was significantly reduced compared to eight weeks ago, but still 507

persists, over two attending physician or above determine: whether the patient can continue 508

to be conservative observation, or pursuant to the disease, patients with the indications for 509

surgery can take burr-hole drainage treatment. Detailed records of the process of 510

medication, treatment should be taken until the end of the 24 weeks of follow-up. 511

3. If the hematoma was no significant change, over two attending physician or above 512

determine: With no indications for surgery, judged by the attending physician and above, 513

whether the patient can continue to be conservative observation; patients with the indications 514

for surgery can take burr-hole drainage treatment. Doctors should be recorded medication, 515

treatment. Detailed records of the process of medication, treatment should be taken until the 516

end of the 24 weeks of follow-up. 517

4. If the hematoma volume increased significantly, the doctor should take targeted 518

therapy in accordance to the treatment of chronic subdural hematoma of various medical 519

centers. The surgical treatment is recommended for patients with indications for surgery. 520

Detailed records of the process of medication, treatment should be taken until the end of 521

the 24 weeks of follow-up. 522

5. During the follow-up, if any hematoma related illness change occured, 523

doctors should make diagnosis and treatment according to the guidelines of each 524

research center for the treatment of chronic subdural hematoma. Detailed records of 525

the process should be taken, serious adverse events should be reported in time. 526




6.4 Drug distribution 527

According to the trial schedule appropriate drug delivery to each research center 528

is carried out , during the period drug will be allocated timely in the light of actual 529

progress. A designated individual of the center is responsible for drug distribution, 530

and records must be maintained throughout this course. In order to ensure timely 531

drug supply, Central Randomization System is used to set up alert of deposit amount. 532

Once the stock is inadequate, the CRA (Clinical research associate) will deliver the 533

drug timely according to the drug packaging numbers the system offered. The 534

applicant could obtain the packaging number from the system and complete the drug 535

distribution only when confirming the arrival of the drugs. Similarly drug adjustment 536

between the centers complies with the operation above. 537

After the screening, investigator logs on the Central Randomization System. 538

Initials, gender, age and other general information of qualified subject are entered for 539

random number application, then the number obtained will be filled in the “random 540

number” column of study reports. Then the drug distributor will apply for the 541

subjects of drug packaging number according to his random number,the system will 542

display this number automatically .The drug distributor needs to input the 543

verification code on the label into the system, once the packaging number displayed 544

is consistent with the one indicated on the label, this drug will be dispensed. 545

6.5 Drug management 546

A designated individual is responsible for inventory, storage, issuance, 547

verification, and records must be maintained throughout the course of the study the 548

records of the quantities of drugs. Study drug require stores at 20 ~ 30 ℃ in the dark. 549

Designated individual (inspectors) responsible for controlling the drug. 550

The test drug is only allowed to administer to enrolled patients with informed 551

consent signed. 552

Host center designate drug inspector. Inspectors make the placebo. After 553




packing is done, the placebo is allocated to the attending doctor, and is responsible 554

for giving the drugs on time. 555

Stored, recovery, and dispensed drugs should be regularly checked. When the 556

trial terminated, all the remained drugs should be check and returned.. 557

6.6 Concomitant medications and treatment 558

1. If the subjects were given drugs potentially interfere with angiogenesis, such 559

glucocorticoids, growth hormone or sex hormone. The details of these drugs 560

(name, the aim of use, duration, dose and treatment) should be recorded on CRF. 561

2. The name of the concomitant medications and the purpose of use should be 562

clearly recorded on CRF. 563

6.7 Drugs prohibited during treatment 564

1. Anticoagulants：Aspirin,warfarin, Clopidogrel, New oral anticoagulants,etc; 565

2. ACTH: Dexamethasone,etc; 566

3. Blood circulation of traditional Chinese medicine: Xuesaitong tablet ,etc; 567

4. ACEI:Perindopril, Captopril, Enalapril,etc. 568

7. Evaluation Parameters 569

7.1 Safety Parameters 570

7.1.1Complications 571

Evaluation of the changes of liver function，limb muscle strength, sensation in 572

the limbs，gastrointestinal reaction and other drug-related symptoms after taking the 573

capsules. 574

7.1.2 Other Adverse Event (AE) and Serious Adverse Event 575




(SAE) 576

7.1.2.1 Physical examination 577

Recording of vital signs (body temperature, heart rate, respiratory rate and 578

blood pressure) and a comprehensive physical examination (general items and 579

recording of positive signs in Dermatologic system, Head, ears, eyes, nose, throat (facial), 580

Respiratory system, Cardiovascular system, Abdomen (including liver and kidney), 581

Musculoskeletal system, Nervous system, Gastrointestinal, Genitourinary, Endocrine, Lymph 582

nodes,others). 583

7.1.2.2 Laboratory examination 584

●Head CT scanning: The volume of hematoma was calculated by the software 585

that comes with the machine. 586

●Head MRI: When the diagnosis of CSDH is difficult, it will be as the 587

alternative examination. 588

●Routine blood test: recording of red blood cells (RBC), hemoglobin (Hb), 589

white blood cells (WBC) and platelet count (PLT). 590

●Serum biochemical parameters: sodium, potassium and chlorine, total 591

cholesterol, triglyceride, alanine aminotransferase(ALT), aspartate 592

aminotransferase(AST), glutamyltransferase, total bilirubin(TB), blood urea 593

nitrogen(BUN), creatinine(Cr); 594

●Coagulation function test: PT、INR、APTT、TT、FIB、D-Dimer； 595

●Urine routine test: PH levels, specific gravity (SG), protein, red blood cells 596

and glucose level in urine. 597

●Electrocardiograph (ECG) 598

7.2 Efficacy Parameters 599

7.2.1 Parameters of the curative effect 600

Main Parameters: 601




The change of hematoma volume（non-enhanced CT scan）at 8th week 602

603

Secondary Parameters: 604

（1）The change of hematoma volume（non-enhanced CT scan）at 4th week 605

during treatment and 12th, 24th week during follow-up. 606

（2）The consciousness score (MGS-GCS) and outcome score (GOS, ADL-BI 607

Scale) in subjects. 608

（3）Changes of neurological symptoms and signs; 609

（4）Changes of routine blood test and coagulation results. 610

7.2.2 Quality control and Quality assurance in effective 611

parameters 612

The unified test parameters, standard operating procedures and quality control 613

procedures should be established among all the laboratories of hospitals joining in this 614

trail. 615

616

8. Termination and Withdrawal of Subjects 617

8.1 The terminal point of this trial 618

The terminal point of this trial is within 48 hours after the end of treatment. At 619

the same time, the investigators should finish a preliminary assessment for subjects. 620

8.2 Withdrawal of Subjects 621

The subjects have the right to withdraw from this trial at any time and for any 622

reasons. The investigators also suspend the subjects at any time according to the 623

decision of subjects. The investigators should comprehensively understand the reason 624

for withdrawal of subjects. 625

The investigators also have the right to tell the subjects to terminate in or 626

withdraw from the trial based on the specific conditions of subjects. It results in the 627




unreliable results that too many subjects withdraw from the trial. As a result, 628

unnecessary withdraw should be avoidable in this trial. 629

The subject early withdrawing from this trail shouldn’t be replaced for other 630

subjects. The ratio on drop off of patients in this trial should be within 20% by 631

control. 632

9. Adverse Event and Serious Adverse Event 633

9.1 Adverse Event 634

The investigators should record the information of adverse event in case report 635

form （CRF）during the treatment. 636

Adverse events is defined as the occurrence of any adverse changes when 637

compared with the baseline (before treatment) after enrollment, including the 638

recurrence of other original disease, whether or not it is related to treatment.Invasive 639

examination itself should not be regarded as adverse events, but the cause of these 640

checks should be recorded . 641

No serious adverse events were be classified as three-tier grade (mild, moderate 642

and severe; seen in the appendix 13.1) and should be report in CRF. Moreover, the 643

relationship between SE and treatment should be assessed ,seen in the appendix 644

13.2. 645

Measures and outcome of treatment for adverse events should be recorded in 646

CRF table. All adverse events should be followed up until the effect that alleviate 647

and stabilize. Supervisors in this trail have the duty on checking the contents 648

recorded in the CRF at any time. 649

9.2 Abnormalities in the clinical laboratory test 650

It is not regarded as SE that the laboratory is abnormal combined with no 651

clinical symptoms and signs. However, this abnormality should be considered in the 652

process of data analysis. Laboratory abnormalities deteriorating or aggravating in the 653




trial obviously illustrated clinical significance and should be given the necessary 654

treatment. Such a condition is considers as SE. At the same time, the investigators 655

should record the curative measures (associated medicine). 656

All laboratory abnormalities should be followed up until the effect that alleviate 657

and stabilize. Ambiguous laboratory abnormalities should be repeated until they are 658

normal and/or can be explanted properly. 659

9.3 Serious Adverse Event（SAE） 660

Serious adverse drug reaction / event refer to one of the following conditions: 661

● results in death; 662

● is life-threatening and results in permanent or significant disability for 663

human body; 664

● lead to permanent injury to the function of organs; 665

● need to go in hospital or prolonged hospitalization. 666

Once the investigators confirmed the occurrence of SAE, they should give a 667

report to secretaries in this trial within 24 hours (Name and cell-phone; Dong Wang, 668

13920732851; Xin Chen: 13752623858; Huijie Wei: 18222918605; Shuo An: 669

13752371400).At the same time, they should fill in a report form for SAE and record 670

event-related information in detail. 671

The investigators should do some evaluation and recording for SAE in CRF as 672

follows: the severity, the relationship with trail product, measures taken for 673

product-related events and the outcomes. 674

10. Data management 675

10.1 Electronic Data Management 676

① The data management of the trial is adopted electronic data management 677

system(DAS for EDC). 678




② Design of CRF: According to the protocol, design the data collection graph, 679

define the procedure of trial and form name and collection data, also come into being 680

the data collection guideline. It will be finalized after sponsors’ examination and 681

approval. 682

③ Electronic CRF construction: According to the protocol and the CRF, data 683

manager will construct the eCRF. 684

④ EDC users can adopt the role authority to double control, all EDC visitors 685

need to fix the account application form. Approved by the sponsors, the system 686

manager will set up the project manager account and authorize. The project manager 687

can construct the accounts for the investigator, CRC, CRA, auditor and data manager, 688

and give them different authorizations to visit EDC. As each investigator can view 689

and edit their own data, the sponsor only can view the EDC, and CRA can view 690

every center’s data but cannot edit the data, only set out the query. 691

⑤Data entry: The PI of each center can appoint the CRC, and the CRC enter 692

the data of CRF into the eCRF promptly and correctly. The eCRF cannot be treated 693

as source document, its source is research document. 694

⑥Data review: When the data is entered, the EDC will proceed the logic 695

review at the same time, and send out the system query immediately. Besides the 696

system query, data manager also check the data manually, and send out the manual 697

query if needed. 698

⑦Source data view（SDV）: The monitor login the DAS for EDC on the site of 699

each center, check the consistence of the data of eCRF and research document 100%, 700

send out the query online at any time if find any question. 701

⑧Answer the query: The investigator can answer the query online, or 702

download the query and answer them offline, then the CRC enter the answer into the 703

EDC. The data manager and monitor can confirm the answer, also can send out the 704

query again if needed until the data is “clean”. 705

⑨Data lock and derivation: All subjects complete the trial, and the documents 706

are entered into the system. After the data library is reviewed and confirmed by the 707

prime investigator, sponsor, statistic analysis and data manager, it will be locked by 708




the data manager. When all data is locked, the data will be derived to the appointed 709

library by the data manager, and handed to the analysis. The locked data cannot be 710

edited, if the problem is found after the data locked, it will be corrected by the 711

statistical analytical procedure. After the data lock, if there is definite evidence to 712

unlock, the investigator and sponsor need to sign the relevant document. 713

⑩Unblind: The trial adopts two folded blinding. After all data is locked, the PI, 714

ST and sponsor will discuss the SAP and unblind, then the random number will be 715

disclosed. After the unblinding, any revise of data will be approved by PI, ST and 716

data manager on the paper. When the statistician analysis is completed, the PI will 717

disclose for the second time. All the procedure will be noted. 718

⑪eCRF keep in files: when the trial is done, the cCRF of each subject will be 719

producted in the form of PDF which will be copied into the disk and reserved for 7 720

years after the trial is finished. 721

⑫ EDC close up: when the trial is completed, data manager will send out the 722

application of closure of EDC. If approved by the sponsor, the DM will cancel the 723

authority of viewing of all accounts, then copy the data totally, close the EDC(as 724

offline). Within 7 years after the trial is completed, if needed to review the data, the 725

center of data manage can reopen the EDC after subscribed. 726

10.2 Make the plan of data manage 727

①Data manage plan is composed by the data manager. 728

②DMP will be treated as the guideline of the whole procedure of data manage, 729

the procedure should operate based on the defined time and method of the DMP. 730

③DMP includes: 731

DMP management, such as ownership, cover provisions and catalog etc. 732

The general situation of the research, such as the research objectives, the 733

overall design, etc. 734

The timeline of the DM, the beginning and finish time of each link should 735

be reflected, the timeline of DM and the whole trial should correspond at 736




the same time. 737

The distribution of users’ authority: includes the EDC administer, DM, 738

investigator, CRC and CRA, etc. 739

Data manage design, includes the data library design and logic verification 740

design. 741

Data manage regulation 742

Data quality control 743

EDC closure 744

Data security measures 745

EDC emergency planning 746

11. Statistical Analysis 747

11.1 Determination of sample size 748

According to the result that 95.7%[21] of the 23 patients treated by atorvastatin 749

have a notable therapeutic effect, if we assume that in a large number of tests, the 750

experiment group obtains an improved therapeutic effect of 80%, while placebo 751

control group obtains 50%. When the test power (1-β) is 80%, we will then need at 752

least 52 cases in each group by reference to the sample size (two sides) for the 753

comparison of two sample rates to be statistically significant. In consideration of the 754

possible falling/important proposal violating occurrence rate during the study 755

(falling elimination proportion is controlled within 20%), the sample size will be 756

expanded to not less than 63 in each group. However, we propose to recruit 200 757

patients with 50% randomly assigned to atorvastatin treatment group and 50% in 758

placebo control group to meet the requirement of China Food and Drug 759

Administration (CFDA) for Drug Registration that the number of cases in treatment 760

group shall not be less than 100 in a Phase II clinical trial. 761




11.2 Analysis of the data set 762

Full Analysis Set（FAS） 763

The full analysis set defines all randomized subjects who take at least one dose 764

of trial medication. When the primary efficacy variable was missing, according to 765

intention to treat principle, the missed data can be carried forward with the previous 766

results. The full analysis set is the main analysis sets. The secondary efficacy 767

variable should be analyzed only using FAS without carrying forward. 768

Per Protocol Set（PPS） 769

The per protocol set defines a subset of the subjects in the full analysis set who 770

meet inclusion criteria, do not meet exclusion criteria and complete the protocol. 771

Those meet the trial protocol, good compliance, complete the CRF required to fill 772

(PP analysis). PP is mainly used for analysis of the primary variable. 773

Safety Set（SS） 774

All subjects were randomized into group，take at least one dose of trial 775

medication and safety evaluation at least once post treatment, constitute the set 776

security analysis of this study. 777

Safety analysis set is the main data set for safety evaluation of the study. 778

11.3 Statistical Methods 779

A detailed statistical analysis will be described in the Statistical analysis plan 780

(SAP). 781

11.3.1 Subject Distribution Analyses 782

The total number, enrolling and completing number of each center should 783

be listed,respectively with data set (FAS，PPS，SS). 784

The reasons for discontinuation as well as the reasons for screen failure will 785

be summarized. 786




11.3.2 Demographic and Baseline Comparability 787

Demographic and efficacy variables at baseline will be summarized using 788

descriptive statistics. 789

Continuous variables will be summarized using mean, median, standard 790

deviation, minimum and maximum. 791

Categorical and ranked variables will be summarized using counts and 792

percentages. 793

The inferential statistical results（P value）will be listed as descriptive 794

results. 795

11.3.3 Efficacy Analyses 796

Analysis of Primary Efficacy Variable 797

The change of hematoma volume from baseline to week 8 will be analyzed 798

using analysis of covariance (ANCOVA), with group as a fixed effect, 799

hematoma baseline value as a covariate. 800

Analysis of Secondary Efficacy Variable 801

The change of MGS-GCS from baseline to week 8 will be analyzed using 802

the t test . 803

GOS will be compared between the two groups using the chi-square test. 804

The change of ADL-BI score from baseline to week 8 will be analyzed 805

using the t test . 806

Changes and measured values in MGS-GCS and ADL-BI score throughout 807

the study will be analyzed using the t test. 808

The number and proportion of subjects whose signs and symptoms had 809

disappeared analyzed using the chi-square test. 810

Changes and measured values in blood routine and cruor variable 811

throughout the study will be analyzed using the t test. 812




11.3.4 Safety Analysis 813

Calculate the incidence of Adverse Events and Adverse Reaction 814

The frequency of AE and AR by body system/organ class will be 815

summarized using counts and percentages. 816

Listing of Adverse Events 817

Listing of Adverse Reaction 818

The counts and percentages of “Normal turn abnormal” or “Abnormal 819

increase” in Laboratory test、ECG、physical examination post treatment. 820

Listing of abnormal values and clinical explanation for Lab test、ECG and 821

physical examination. 822

11.4 Statistical software and general requirements 823

All statistical analyses will be performed using SAS version 9.3. 824

Two-sided confidence intervals set at 95 percent should be used to show 825

Superiority test. 826

Data will be analyzed by two-sided analysis; p value less than 0.05 will be 827

considered statistical significance. 828

11.5 Interim Analysis 829

Interim analysis will not be conducted. 830

831




12. Trial Management 832

12.1 Ethics 833

The investigators have the responsibility to summit the protocol of clinical trials 834

and the copies of the documents like as the informed consent to ethic commission in 835

order to obtain independent approval documents of the clinical trial carried out. 836

The documents of approval from the ethics committee should be obtained 837

before the start of the clinical trial. These documents need to be delivered to the 838

investigators in written form. After that a copy of the approval document will be 839

provided to sponsor by the investigators. The approval documents from ethics 840

committee should be accompanied by the name list of ethics committee members 841

and their respective responsibilities. 842

Any safety-related issues in clinical trial must be promptly reported to ethics 843

committee, which includes the protocol of clinical trials, modification of patient 844

information pages and serious adverse reaction. It also must be reported to the ethics 845

committee that the clinical trial end in or early terminate. 846

12.2 Informed consent and data protection agreement 847

The investigators have the responsibility to explain the purpose, methods, 848

benefits and potential risk of the trial for each person. Also the investigators should 849

obtain the informed consent signed by subjects. Written informed consent must be 850

obtained before performing any procedures related with clinical trial. The informed 851

consent must be signed by their parents, legal guardians or protectors for those 852

subjects who didn’t sign the informed consent due to any causes. The 853

subjects/patients must also permit clinical research associate/auditor/health survey 854

organizations in checking original clinical trial-related data obtained by the means of 855

signing informed consent. As a result, we can know the reliability of results in 856




clinical research. 857

Each patient’s information, such as address and telephone number, should be 858

collected in detail. And the doctor should give the patient his or her phone number, 859

so that the patient will find the doctor when the illness state changes, which will be 860

helpful for the doctor too. 861

The informed consent signed and dated by the subject personally should be kept 862

properly by the researchers，and the documents should be attached in the CRF and 863

the treatment records of subjects. 864

12.3 Withdraw from clinical study 865

The researchers have right to ask the subjects to withdraw from clinical trials in 866

the circumstances related to their interests, including complications, AE or treatment 867

failure. No matter how and when the subjects withdraw, the researchers should 868

indicate the reasons. All the cases withdrew from clinical trials for complication or 869

AE should be explained in detail in the CRF with all the related materials. 870

Reviews should be made in one to three days after administration. 871

12.4 Subjects Privacy 872

The researchers should protect and maintain the privacy of the subjects. Only 873

the subjects’ numbers instead of names or admission numbers can be used for 874

identification in all the documents submitted to the sponsor. While the grouped table 875

recording correspondence of the subjects’ names and numbers should be kept 876

properly and confidentially by the researchers, and not be submitted to the sponsor. 877

12.5 Modification of the clinical trial protocol 878

The clinical trial scheme should be made and signed by researchers and sponsor 879

together and approved by the ethics committee before testing. 880

Anything went wrong during the testing be implementing, the modification of 881




the scheme should be put forward by the sponsor and consulted by polycentric 882

coordination committee. Then the suggestions for modification should be submitted 883

to sponsor and attending centers in writing and signed, which should be approved by 884

the ethics committee before the testing starting again. 885

12.6 CRF 886

The CRFs should be kept completely and filled precisely by the researchers. 887

Each CRF records only one subject’s documents, and all the wrong data and words 888

should not be altered but marked with a single line and refilled the right ones with 889

the researchers’ signs and amend dates on the side. 890

12.7 Original records certification 891

Researchers must be due with the data collected during the research 892

appropriately to make sure that the rights and privacy of the subjects be protected. 893

Besides, controllers, comptrollers and inspectors should be permitted to check and 894

verify the materials in order to confirm the accuracy of the original data and to know 895

the progress of the research. If the original data failed to be confirmed, researchers 896

should agree to assist controllers, comptrollers and inspectors with the further 897

verifying of the quality of the data. 898

12.8 Publication 899

The data of each center may not be published separately before the final results 900

of the whole multicenter clinical research have been published. 901

Before that, the sponsor keeps the right to check and approve the first draft. 902

12.9 Documents on file 903

According to related laws and regulations, researchers should keep the clinical 904

original records appropriately. And all the clinical research duplicates should be kept 905




by the time the research have ended for 5 years at least. 906

12.10Quality control and assurance 907

All the drugs and materials in the clinical research must be used on the premise 908

of quality control. Meanwhile, the sponsor, the authorized or the related medical 909

administration are entitled to check and approve the research in order to make sure 910

that the research data be recorded veritably and research be carried through as 911

predetermined. All the subjects will be informed the process of verify during the 912

research on condition that the privacy and data of the subjects be protected strictly. 913

12.11Clinical research controller 914

The clinical trial monitors take responsibility to be familiar with all the 915

researchers involved and the key member of each process including dispensing in the 916

research. And the work of the clinical trial center must be observed regularly, each 917

once at least at the point of the first grouping and the mid-time and post-time of each 918

trial. 919

The monitors should verify that whether the clinic trial is carried on in 920

accordance with the research approach and due with the issues arisen corporately 921

with the researchers. They also take the responsibility to compare the research 922

records with the original medical ones to make sure of the authenticity of documents. 923

The inspecting results of the original data should be described in detail 924

according to the standard operating procedures, which should be kept confidentially. 925

All the informed consents signed for recruitment must be verified. 926

12.12Research schedule 927

1. From Dec. 2012 to Apr. 2013, research approach and adjunctive devised 928

first draft was completed and the first working conference was held to 929

discuss the revised protocols. 930




2. From Apr. 2013 to Sep. 2013, the protocols was submitted to and approved 931

by the ethics committee. The clinical work started after preclinical 932

preparation. 933

3. From Oct. 2013 to Jan.2014, initiation meeting will be held for protocol 934

training. 935

4. From Feb.2014 to Dec. 2015, the treatment research will be completed and 936

the collected results were assessed primarily. 937

5. From Jan. 1, 2016 to Jun. 30, 2016, all the follow-up visits will be 938

completed to make clinical assess. 939

6. The statistics by the third party will be opened for the first uncovering in 940

July 2016, and the second one will be made in July 2016 when the results 941

announced finally. 942

7. The summarized and perfected views will be submitted to the well-known 943

clinical research journals abroad in Oct. 2016. 944

12.13Clinical research institutions 945

1). Sponsor 946

Organization: Department of Neurosurgery Tianjin Medical University General 947

Hospital 948

Address: No. 154 Anshan Road, Tianjin 949

Postcode：300052 950

Telephone：022-60817448 951

2) Participating Organization 952

According to the contract. 953

3) Statistic Analysis 954


Address: 26 haoyuan, Yuetan south Street, Xicheng District, Beijing 956


Telephone：010-68522081 958




4)Contract Research Organization: 959


Address: 26 haoyuan, Yuetan south Street, Xicheng District, Beijing 961


Telephone：010-68522081 963

5) Research Documentation preservation Organization 964

The original data should be preserved when the research have been ended for 965

five years at least. 966

967




13. Appendix 968

13.1 Adverse Event Degree 969

Adverse events should divided into three degrees according to the following 970

standards: 971

Minor: It is usually transient and uninfluenced to normal activity. 972

Moderate: It induces discomfort and influences normal activity, and the subjects 973

could tolerate the obvious symptoms. No need to withdraw. 974

Severe: The subjects can’t do normal activity, and the subjects can’t tolerate the 975

conspicuous symptoms. Need to withdraw. 976

977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996




13.2 Relativity Between Adverse Events and the Drug 997

Estimation 998

The relationship between adverse events and the drug should be assessed as 999

related, probably related, possibly related, possibly unrelated, and not related, 1000

and the summation of the former three make up incidence rate of adverse events. 1001

The causal relationship should be assessed according to the following five 1002

principles (Center for Drug Reevaluation of SDA, 2002). 1003

1. Whether there is time relationship between the drug and adverse events? 1004

2. Whether the adverse event is one of the known types? 1005

3. Whether the adverse effect disappears or relieves after withdraw or reduce 1006

of the drug? 1007

4. Whether the similar reaction would reappear when the suspicious drug had 1008

been used again? 1009

5. Whether the adverse effect could be accounted for by the usage of the drug 1010

combination, the progress of the disease or other treatment effect? 1011

The relationship between adverse events and the drug: 1012

1 2 3 4 5 Related ＋＋＋＋ — Probably related ＋＋＋？ — Possibly related ＋＋ ± ？ ± Possibly unrelated ＋ — ± ？ ± Not related — — — — ＋

Introduction：’+’ positive, ‘-‘ negative, ‘±’ uncertain, ‘?’ unknown 1013




13.3 MGS-GCS 1014

Patients were evaluated using the Glasgow Coma Scale and Markwalder’s Grading 1015

Scale 1016

Patient’s Grade Glasgow Coma Scale Markwalder’s Grading Scale

Grade 0 Glasgow Coma Scale score of 15 Normal neurological status without any symptoms

Grade 1 Glasgow Coma Scale score of 15 Without neurological deficits, but with symptoms such as headache or unsteady gait

Grade 2 Glasgow Coma Scale score of 13 to 14

Focal neurological deficits, such as drowsiness or disorientation, or variable neurological deficits, such as hemiparesis

Grade 3 Glasgow Coma Scale score of 9 to 12

With stupor but appropriate responses to noxious stimuli and several focal neurological signs such as hemiplegia

Grade 4 Glasgow Coma Scale score of less than 9

Coma with absent motor responses to noxious stimuli and decerebrate or decorticate posturing

Only patients with Grade 0-2 CSDH were selected for atorvastatin treatment in this study. References： 1017 1. Markwalder TM, Steinsiepe KF, Rohner M, Reichenbach W, Markwalder H. 1018

The course of chronic subdural hematomas after burr-hole craniostomy and 1019 closed-system drainage. Journal of neurosurgery. Sep 1981;55(3):390-396. 1020

2. Sun TF, Boet R, Poon WS. Non-surgical primary treatment of chronic subdural 1021 haematoma: Preliminary results of using dexamethasone. British journal of 1022 neurosurgery. Aug 2005;19(4):327-333. 1023

1024

1025

1026

1027

1028

1029

1030

1031

1032




13.4 GCS 1033

Glasgow Coma Scale

1 2 3 4 5 6

Eye Does not open eyes

Opens eyes in response to

painful stimuli

Opens eyes in response

to voice

Opens eyes spontaneousl

y N/A N/A

Verbal

Makes no sounds

Incomprehensible sounds

Utters inappropriat

e words

Confused, disoriented

Oriented,

converses

normally

N/A

Motor

Makes no movement

s

Extension to painful stimuli (decerebrate

response)

Abnormal flexion to

painful stimuli

(decerebrate response)

Flexion / Withdrawal to painful

stimuli

Localize spainful stimuli

Obeys command

s

The scale is composed of three tests:eye,verbal and motor responses. The three values separately 1034

as well as their sum are considered. The lowest possible GCS (the sum) is 3 (deep coma or 1035

death), while the highest is 15 (fully awake person). 1036

1037 1038 1039 1040 1041 1042 1043 1044 1045




13.5 ADL-BI 1046

ADL-BI Prior to enrollment, the first seven days, the first 4 weeks, 8 weeks, 12 weeks and 24 weeks: report the

best ADL-BI score results, assess the situation possiblly in the case which does not be interfered.

Date (DD/MM/YYYY ): |___|___| / |___|___|/ |___|___|___|___|

Time (HH:MM) (24-hour clock): |___|___| : |___|___|

Not done: □No □Yes

1. Eating ability

0 Score □ Great help 5 Scores □ Some independent some help 10 Scores □ Independent

2. Bathing ability 0 Score □ Some independent some help 5 Scores □ Independent

3. cleaned (wash, brush your teeth, shave, hair) ability

0 Score □ Some independent some help

5 Scores □ Independent

4. Clothing (socks, buttons) capability


5. Defecating ability 0 Score □ Great help (uncontrolled) 5 Scores □ Some independent some help (uncontrolled 1 time/1week) 10 Scores □ Independent

6. Urinating ability 0 Score □ Great help (uncontrolled) 5 Scores □ Some independent some help (uncontrolled 1 time/24 h) 10 Scores □ Independent

7. Using the toilet (wipe, sorting clothes, flush)

capacity


8. Transferring bed or chair ability

0 Score □ Totally dependent 5 Scores □ Great help 10 Scores □ Some independent some help 15 Scores □ Independent

9. Walking 45 meters ability

0 Score □ Totally dependent 5 Scores □ Great help 10 Scores □ Some independent some help 15 Scores □ Independent

10. Upstairs and downstairs ability

0 Score □ Great help 5 Scores □ Some independent some help




10 Scores □ Independent ADL-BI total scores □□ Scores

Assessor

□ Neurosurgeon □ Emergency doctor □ Intensive care physicians □ Nurse □ Other (Please specify)

[If assessor is ‘other’,please specify] Description : 1. Dinner: Independent eating is referred the independent patient within the normal time eats prepared food, including any normal diet (not only soft food), food can be done by other people; their food, hold rice, stir, cutting food, etc. can be completed independently, for 10 scores; If their food, hold rice, stirring, cutting food and other need among small help to complete, for 5 scores, otherwise for 0 score. 2. Bath: to access the bathroom without guidance, supervision and assistance, scrub by himself, shower does not need help or supervision, for 5 scores, otherwise for 0 score. 3. Grooming: referred to the situation within 24-48 hours, to complete facing, hairing, brushing teeth, shaving and other personal hygiene, with caregivers doing something such as squeeze toothpaste, ready for water, for 5 minutes, otherwise for 0 score. 4. Dressing: referred to the same ability as before the disease to wear off all kinds of clothes, footwear, etc., including lining buckle, zipperring and shoing, etc., for 10 scores; lining buckle, lacing, zipperring and other complex functions need some help with independently putting on coat, shoes and other simple functions for 5 scores, otherwise for 0 score. 5. Bowel control: referred to the week; complete control, for 10 scores; occasional incontinence (less than or equal to 1 time per week), for 5 scoress; incontinence or coma more than 1 time per week, for 0 score. 6. Urine control: referred to the 24-48 hours; complete control, for 10 scores; occasional incontinence (less than or equal to 1 time per 24 hours, more than once a week), for 5 scores; frequent incontinence (more than 1 per 24 hours), for 0 score. Catheterization patients are regards as incontinence. 7. The toilet: to access toilet or commode by himself, without dressing or sanitating by others, for 10 scores; some hel, for 5 points; major functions such as de- dressing and sanitating need help, for 0 score. 8. Seat /bed transporter: patient can move from the bed to the chair and return safetily and independently, for 15 scores; need a person or language guide to ensure the safety, for 10 scores; need 2 or a strong and skilled people to help, for 5scores; can not sit up, or need help more than 2 people, for 0 score. 9. Walk: referred to at home or in the ward, l use aids (including crutches, but not include tools such as wheelchair, etc.) in the hospita, walk independently 50 meters without the supervision and care, for 15 scores; need an untrained person to help (physical or verbal guidance), walk 50 meters with the supervision and care, for 10 scores; act independently in a wheelchair, walk 50 meters with a wheelchair independently, for 5 scores; otherwise for 0 score. 10. Up and down the stairs: up and down stairs independently, including by an auxiliary device (such as




crutches, etc.), for 10 scores, o up and down stairs with some help(eg, arm, etc.) or the supervision can be done, for 5 scores; otherwise for 0 score.

1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088




13.6 GOS (Glasgow Outcome Score) 1089

Score Degree Description

5 Good

recovery

This implies resumpution of normal life even

though there may be minor defects.

4 Moderate

disability

Disability but can live independently; work under

protection.

3 Severe

disability

Awake, disability, need to take care of daily life.

2 Persistent

vegetative

state

Only the minimum reaction (such as with

sleep/wake cycles, can open eyes)

1 Death Death 1090 1091 References： 1092 Assessment of outcome after severe brain damage “Jennett B. Bond M”. Lancet. 1975 Mar 1; 1093 1(7905): 480-4. 1094 1095 1096 1097 1098 1099




14. Signature of each organization 1100

involved in the clinical trial 1101

Clinical trial: Multi-center randomized and double-blind 1102

controlled clinical trial on therapy of chronic subdural hematoma 1103

by Atorvastatin 1104

All the involved researchers have approved all the clauses, and will carry 1105

out the protocol strictly according to the GCP and Helsinki Declaration. 1106

1107

Sponsor Unit ：Tianjin medical university, General hospital 1108

Signature of PI： Date：___（day）___(month) _____ (year) 1109

1110

Research Institution： 1111

Signature of PI：_______________ Date：___（day）___(month) _____ (year) 1112


































1143

Statistical Analysis: Beijing Stemexcel Technology Co.,Ltd 1144


1146

Contract Research Organization: Beijing Stemexcel Technology Co.,Ltd 1147


1149

1150

1151

1152

1153

1154




15. References 1155

1. Tsai TH, Lieu AS, Hwang SL, Huang TY, Hwang YF. A comparative study of 1156

the patients with bilateral or unilateral chronic subdural hematoma: precipitating 1157

factors and postoperative outcomes. J Trauma 2010;68:571-575 1158

2. Suyuan Yang, Dashi Zhi. Neurosurgery. Beijing: People’s Medical Publishing 1159

House.2007:892-895. 1160

3. Santarius T, Hutchinson PJ. Chronic subdural haematoma: time to rationalize 1161

treatment? Br J Neurosurg 2004; 18: 328-332. 1162

4. Gannon WE, Cook AW, Browder EJ. Resolving subdural collections. J 1163

Neurosurg 1962; 19: 865-9. 1164

5. Parlato C, Guarracino A, Moraci A. Sponta- neous resolution of chronic 1165

subdural hematoma. Surg Neurol 2000;35:312-7. 1166

6. Naganuma H, Fukamachi A, Kawakami M, Misumi S, Nakajima H, Wakao T. 1167

Spontaneous resolution of chronic subdural hematomas. Neurosurgery. 1168

1986;19:794-8. 1169

7. Santarius T, Hutchinson PJ. Chronic subdural haematoma: time to rationalize 1170

treatment? Br J Neurosurg. 2004 Aug;18(4):328-32. 1171

8. Okada Y, Akai T, Okamoto K, Iida T, Takata H, Iizuka H. A comparative study 1172

of the treatment of chronic subdural hematoma--burr hole drainage versus burr 1173

hole irrigation. Surg Neurol 2002; 57: 405-409; discussion 410. 1174

9. Bershad EM, Farhadi S, Suri MF, et al. Coagulopathy and inhospital deaths in 1175

patients with acute subdural hematoma. J Neurosurg 2008; 109: 664-669. 1176

10. Miranda LB, Braxton E, Hobbs J, et al. Chronic subdural hematoma in the 1177

elderly: Not a benign disease. J Neurosurg.114:72-76. 1178

11. Zhiqing Tao. Etiology and pathogenesis of Chronic subdural hematoma. Chinese Journal 1179

of Neurosurgerical Disease Research. 2009,2:190-192. 1180

12. Hohenstein A, Erber R, Schilling L, et al. Increased mrna expression of vegf 1181

within the hematoma and imbalance of angiopoietin-1 and -2 mrna within the 1182




neomembranes of chronic subdural hematoma. J Neurotrauma. 2005; 22: 1183

518-528. 1184

13. Stanisic M, Lyngstadaas SP, Pripp AH, et al.Chemokines as markers of local 1185

inflammation and angiogenesis in patients with chronic subdural hematoma: a 1186

prospective study.Acta Neurochir (Wien). 2012, 154(1):113-20. 1187

14. Stanisic M, Aasen AO, Pripp AH, et al.Local and systemic pro-inflammatory 1188

and anti-inflammatory cytokine patterns in patients with chronic subdural 1189

hematoma: a prospective study.Inflamm Res. 2012,61(8):845-52. 1190

15. Delgado-López PD, Martín-Velasco V, Castilla-Díez JM, et al. Dexamethasone 1191

treatment in chronic subdural haematoma.Neurocirugia. 2009, 20(4):346-59. 1192

16. Wang D, Jiang R, Liu L, Dong JF, Zhang JN. Membrane neovascularization and 1193

drainage of subdural hematoma in a rat model.J Neurotrauma. 2010, 1194

27:1489-98. 1195

17. Araújo FA, Rocha MA, Mendes JB, et al. Atorvastatin inhibits inflammatory 1196

angiogenesis in mice through down regulation of VEGF, TNF-alpha and 1197

TGF-beta1. Biomed Pharmacother. 2010,64:29-34. 1198

18. Buttmann M, Lorenz A, Weishaupt A, et al. Atorvastatin partially prevent1199

s an inflammatory barrier breakdown of cultured human brain endothelial 1200

cells at a pharmacologically relevant concentration. J Neurochem. 2007, 11201

02(4):1001-8. 1202

19. Lu D, Qu C, Goussev A, Jiang H, et al. Statins increase neurogenesis in the 1203

dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, 1204

and improve spatial learning in rat after traumatic brain injury. J Neurotrauma. 1205

2007, 24: 1132-46. 1206

20. Weis M, Heeschen C, Glassford AJ, et al. Statins have biphasic effects on 1207

angiogenesis. Circulation, 2002, 105:739–745. 1208

21. Wang D, Li T, Tian Y, et al. Effects of atorvastatin on chronic subdural 1209

hematoma: A preliminary report from three medical centers. Journal of the 1210

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