More information © 2014 Denver Public Health The (frequently long, circuitous, and bumpy) trip from clinical problems to clinical trials Bill Burman Denver

© 2014 Denver Public Health

The (frequently long, circuitous, and bumpy) trip from clinical

problems to clinical trials

Bill BurmanDenver Public Health


One view of clinical trials


Clinical trials: cautionary notes

• Time for a Phase 3 trial – a decade (or more!)– Trial development – 1 to 5 years, trial conduct – 4 to 8

years, trial analysis – 1 to 2 years– Will the question be relevant in 10 years?

• Cost of classic clinical trials (GCP, professional site monitoring): – $5-25,000 per patient/year – For a trial of 1000 patients, $5 million to $25 million per

year of the trial

• Opportunity cost– Limited funding for TB clinical trials – Is this a durable and

critical question?


Another view of clinical trials…


Problems of not doing clinical trials: When to start ART

• When to start antiretroviral therapy (ART) – classic case for a randomized trial– Important clinical and programmatic question– Randomization possible at the level of the

patient

• Challenges for “When to start” study– Shifting equipoise– Concerns about feasibility


Shifting recommendations for “When to start ART” – IAS USA panel

> 500 VL>30K

VL>5K VL>10K

350-500

VL>5K VL>5K

200-350

<200

CD4 1996

1998

2000

2002

2004

2006

2008

2010



> 500 VL>30K VL>5K VL>10K

350-500

VL>5K VL>5K

200-350

<200

CD4 1996

1998

2000

2002

2004

2006

2008

2010

“It is questionable whether a randomized trial to study the issue of When to Start will ever be feasible.” 2002 guidelines



> 500 VL>30K VL>5K VL>10K

350-500

VL>5K VL>5K

200-350

<200

CD4 1996

1998

2000

2002

2004

2006

2008

2010

“It is questionable whether a randomized trial to study the issue of When to Start will ever be feasible.” 2002 guidelines


When to start ART: Potential of ART

• Prevent classic AIDS outcomes• Prevent irreversible loss of immune

function (clonal deletion)• Prevent other serious events:

– cardiovascular, renal, and hepatic events– other cancers– neurocognitive dysfunction

• Prevent HIV transmission


When to start ART: Problems of ART

• Short-term side effects – diarrhea, rash, etc.• Long-term metabolic effects

– Hyperlipidemia, bone loss– Renal and hepatic toxicity

• Behavioral disinhibition – leading to increased risk of transmission

• Acquired drug resistance, transmitted resistance• Cost of antiretroviral therapy – drugs, monitoring,

increased clinical care


SMART study – ART-naïve or off ART for > 6 months

• CD4 > 350• Randomized

– Immediate ART– Deferred ART: start when CD4 < 250 – ART: physician/patient choice

• 477 enrolled (of 5472 in overall trial)– 249 ART-naïve– 225 off ART for > 6 months

• Median follow-up – 18 months


Outcomes of SMART sub-study of “When to Start”

0

1

2

3

4

5

6

7

8

AIDS/ death Serious non-AIDS Composite

Rate

per

100 p

ers

on-y

ears

< 250 > 350

P = 0.02P = 0.01

P = 0.002

SMART Study Group. J Infect Dis 2008; 197: 1133-44


Lessons of the “When to start ART” controversy

• > 15 years of controversy not resolved by many, increasingly large and increasingly sophisticated observational studies

• Clarity provided by two relatively small randomized clinical trials (combined n = 1293, with median follow-up for < 2 years)

• Recommendations for common, important clinical decisions should be based on randomized trials


Examples of the problems of not doing clinical trials: TB


Examples of the problems of not doing clinical trials: TB

• Sub-optimal treatments– Dosing of 1st (and 2nd) line TB drug in children– MDR-TB regimens without clarity on critical questions

(e.g., number of drugs, length of aminoglycoside use, selection of fluoroquinolone)

• Uncertainty about managing toxicity– Drug-related liver injury– Dosing of PZA, use of PZA in higher-risk patients

• Key details about 1st-line therapy– Optimal duration– Intermittency – when during treatment, degree


Getting started

• Identify a compelling clinical problem – important in terms of diagnosis, treatment effectiveness, toxicity, prevention, population control

• Find relevant observational studies– Current practices – Key outcomes: definitions, rates, associated factors, estimation of the

effect size of an intervention

• Consider doing research on what to do research on– Survey clinicians: key questions, areas of equipoise– Survey patients: outcomes of TB treatment that are important to

patients– Formal decision analysis – cost-effectiveness modeling of various

forms of treatment of latent TB


Getting started


• Find relevant observational studies– Current practices – Key outcomes: definitions, rates, associated factors, estimation of the






Getting started


• Find relevant observational studies– Current practices (sometimes substantially different from guidelines)– Key outcomes: definitions, rates, associated factors, estimation of the






Getting started


• Find relevant observational studies– Current practices (sometimes substantially different from guidelines)– Key outcomes: definitions, rates, associated factors, estimation of the



patients– Formal decision analysis – for example, cost-effectiveness modeling of

various forms of treatment of latent TB


Trials of treatment-shortening with fluoroquinolones

• Rationale– Mouse model studies – moxifloxacin allowed

treatment shortening to 4 months, especially if substituted for INH

– Improved treatment completion, leading to improved TB control

– Fluoroquinolones are well-tolerated, known to be safe• Three Phase 3 trials undertaken

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6

Duration of treatment (mos.)

Lo

g C

FU

in

en

tire

lu

ng

Untreated

2RHZ+4RH

2RHZM+4RHM

2RMZ+4RM

Activity of moxifloxacin in combination therapy in a mouse model of TB

2.5 logs

Am J Respir Crit Care Med 2004; 164:421-6


Concerns about fluoroquinolones for treatment-shortening

• Toxicity/tolerability– Uncertainty about safety in pregnancy, children, and

the elderly– Concerns about possible cardiotoxicity from moxi– Selection for resistance in M. tuberculosis might limit

2nd-line regimen potency– Broad activity against common bacterial pathogens –

selection for resistant strains, C. difficile

• Lack of consistent activity in Phase 2 trials• Opportunity cost


Effect of moxifloxacin on 2-month sputum culture conversion

Study 27 South Africa Brazil Study 280

10

20

30

40

50

60

70

80

90

100

71

82 80

60

7164 63

55

Moxi Comparator EMB


Effect of moxifloxacin on 2-month sputum culture conversion

Study 27 South Africa Brazil Study 280

10

20

30

40

50

60

70

80

90

100

71

82 80

60

7164 63

55

Moxi Comparator

N = 336N = 150

N = 102

N = 443

EMB


Treatment-shortening using moxifloxacin for drug-susceptible active disease

Gillespie S, et al. N Engl J Med 2014; 371: 1677-87

Relapses• IRZE – 12 (2%)• IRZM – 46 (9%)• MRZE – 64 (12%)

2-month conversion• IRZE – 83%• IRZM – 85%• MRZE – 87%


TB clinical trials: drug-susceptible TB

• Lessons from the past decade– Regimens for drug-susceptible disease must be

applicable to women of child-bearing age and children– Don’t start Phase 3 trials of treatment-shortening

without compelling results from Phase 2 – Is treatment-shortening to 4 months the most

important question in treatment of drug-susceptible TB?

– We are far to quick to conclude that a new regimen is “safe and well-tolerated”


Suppression of ventricular ectopy after acute MI

• Sudden death is common after a heart attack• Ventricular ectopy is a risk factor for sudden death• Drugs are available that markedly suppress ventricular ectopy• In a pilot randomized trial, these drugs were well-tolerated• Clinicians started to prescribe these drugs to suppress ventricular ectopy


Efficacy in suppressing ventricular ectopy

0

10

20

30

40

50

60

70

80

90

flecainide encainide moricizine placebo

% o

f p

ati

en

ts w

ith

> 7

0%

su

pp

ressio

n

Am J Cardiol 1988;61:501-9


Tolerability in Phase 2

Encainide(n = 99)

Flecainide(n = 103)

Moricizine(n = 98)

Placebo(m = 100)

Death 0 0 0 0

CHF 1 0 0 0

MI 0 0 1 2

Other SAE 0 1 0 0

Drug stopped

2 3 6 7

Am J Cardiol 1988;61:501-9


Effect of flecainide, encainide on mortality - data from Phase 3 (n = 1500)

0123456789

total mortality cardiac mortality

Mo

rtal

ity

active drug placebo

N Engl J Med 1989;321:406-12


Lessons of the CAST study

• Fixing a surrogate marker may not fix the disease and may even exacerbate it

• Other examples: – post-menopausal hormone replacement therapy and

CVD risk– effect of antiretroviral therapy on CVD risk– effect of EPO on anemia in ESRD

• Sample sizes in most clinical trials are inadequate to detect unusual but serious adverse effects


TB clinical trials: drug-susceptible TB

• Lessons from the past decade– Regimens for drug-susceptible disease must be

applicable to women of child-bearing age and children– Don’t start Phase 3 trials of treatment-shortening

without compelling results from Phase 2 – We are far to quick to conclude that a new regimen is

“safe and well-tolerated”– Is treatment-shortening to 4 months the most

important question in treatment of drug-susceptible TB?


Prospective study of tolerability of treatment for pulmonary TB

• Multicenter prospective study – 4 regions of China, sampling scheme to assure representative sample of patients with pulmonary TB

• Baseline survey and labs• Treatment: IRZE for initial treatment, Strep added for

re-treatment• Symptom diary during treatment • Repeat labs at 2 months• Adverse events and TB treatment outcomes

evaluated using standardized criteria


Demographic and clinical characteristics of the cohort

Parameter Number (% of 4304)Median age (IQR) 42 (29 – 55)Male/female 3082 / 1227TB treatment history Primary 3556 (83% Re-treatment 748 (17%)Hep B S Ag positive 469 (11%)History of drug reaction 118 (3%)Hepatobiliary disease 23 (0.5%)Gastroenteropathy 40 (1%)Diabetes 51 (1%)Other medical illnesses 103 (2%)

Lv Z, et al. PLoS One 2013


Adverse drug reactions

• Frequency– 766 (17%) had an adverse reaction, 1.4% had a serious

adverse reaction, 1% hospitalized– Liver dysfunction – 6.3%, 0.6% had serious hepatotoxicity

• Effect on TB treatment regimen– 43% of those with adverse reaction had regimen changed,

5% stopped all TB treatment

• Effect on TB treatment outcomes– 2.8% with adverse reaction had unsuccessful TB treatment

(vs. 1% of those without an adverse reaction)– 19% of all unsuccessful outcomes attributed to adverse

reactions









reactions









reactions


Comparison of hepatotoxicity risk among antimicrobial agents

Drug Hepatotoxicity incidence per 100,000

courses

Comments

Amox-clav * 1-17 Generally benign

Telithromycin * 17 Withdrawn from the market

Levofloxacin * 0.02

Trovofloxacin * 6 Withdrawn from the market

Rifampin 70 Annals Intern Med 2008; 149: 694

Isoniazid 380 Annals Intern Med 2008; 149: 694

Pyrazinamide 430 Ann Intern Med 2002; 137: 640-7

* Andrade R, Tulkens PM. J Antimicrob Chemother 2011; 66: 141-6

In population-based studies, TB drugs are among the most common causes of serious drug-related hepatotoxicity (Aliment Pharmacol Ther 2010;31:1200, Gastroenterol 2008;135:1924)


Changes in age-distribution among cases of active TB (Hong Kong)

Wu P, et al. PLoS One, 2010

As transmission decreases, active TB becomes increasingly a disease of the elderly


Age-specific rates of active TB, by WHO region

http://www.who.int/tb/publications/global_report/en/


Toxicity considerations in treatment of drug-susceptible disease

• INH and PZA are much more hepatotoxic than antibiotics that have been removed from the market

• The new norm of TB: – Elderly, increased prevalence of comorbid disease– Higher risk of adverse effects, including hepatitis and CVD

• Encourage enrollment of elderly and “complicated patients” into TB clinical trials

• Is it time for trials comparing interventions for toxicity avoidance?


Endpoints – How to define “better” (or “not inferior”)

• Clinical endpoints (TB, relapse, death)– Infrequent events in TB patients– Postulated differences in clinical event rates (treatment

effect size) may be small– Infrequent events analyzed as dichotomous endpoints

+ small effect size = large sample sizes• Surrogate markers (EBA, effect on transaminases,

cholesterol, etc.)– Continuous variables with large dynamic range =

markedly smaller sample size


Endpoints – the lessons of CAST and SMART

• Surrogate markers – quite reasonable for initial studies, to generate hypotheses• Effects of interventions may be much more complex than their effect on one or more surrogate markers• Surrogate markers should not be relied on as the basis for major clinical decisions/policies


Dealing with complex clinical situations

• Heterogeneity of “MDR-TB”– Primary vs. acquired– Degree of resistance to 2nd-line drugs– Different definitions of “resistance”– Limitations posed by intolerance to 2nd-line drugs– Severity of pulmonary disease

• Common conclusion – Impossible to do clinical trials for MDR-TB


Example of “optimized background regimen” design for MDR-HIV

• Study population– Prior therapy with NRTI, NNRTI, PI– Virological failure of current therapy (VL > 5000)

• Randomization– Optimized Background Regimen (OBR) chosen by enrolling clinician – could include other investigational drugs– OBR + T-20 (enfuvirtide)


T-20 trial: baseline characteristics

Characteristic

Previous ART > 5 PIs Lopinavr/R Tenofovir

Viral load < 40,000 > 40,000

T-20

49%39%3%

20%80%

Control

39%28%

0

20%80%

N Engl J Med 2003;348:2175-85


T-20 trial: baseline characteristics

Characteristic

Genotypic susc. Score 0 1-2 3-4 >5

Use of other investigational agents Lopinavir/R Tenofovir

T-20

16%52%28%4%

62%8%

Control

13%56%27%2%

62%7%

N Engl J Med 2003;348:2175-85


T-20 trial – efficacy results

N Engl J Med 2003;348:2175-85, N Engl J Med 2003;358:

N = 501


T-20 trial – efficacy results from paired trials

N Engl J Med 2003;348:2175-85, N Engl J Med 2003;358:

N = 501


Clinical trials for complex problems

• Don’t try to over-simplify life – manage complexity, don’t try to eliminate it

• We under-estimate the power of randomization to deal with clinical heterogeneity


Alternate trial designs

• Behavioral or system-level interventions (e.g., DOT vs. SAT, availability of rapid susceptibility testing, community-based testing to decrease TB transmission) – Cluster-randomized– Stepped-wedge trial


Alternate trial designs

• Behavioral or system-level interventions (e.g., DOT vs. SAT, availability of rapid susceptibility testing, community-based testing to decrease TB transmission) – Cluster-randomized– Stepped-wedge trial


Andrew Nunn’s rules for clinical trials

1. Ask important questions2. Use simple designs3. Enroll enough patients to answer the

questionMy corollaries• Don’t rush to trial design; do research

on what to do research on• Seek out – don’t avoid – a wide range

of feedback on the design are worthy


Andrew Nunn’s rules for clinical trials

1. Ask important questions2. Use simple designs3. Enroll enough patients to answer the

questionMy corollaries• Don’t rush to trial design; do research

on what to do research on• Seek out – don’t avoid – a wide range

of feedback on the design are worthy


Closing thoughts

• Clinical trials– Not for the faint of heart– Not for the impatient– Not for the loner -

collaborative exercise, political process

– But the team can accomplish something big


Closing thoughts

• Clinical trials– Not for the faint of heart– Not for the impatient– Not for the loner -

collaborative exercise, political process

– But the team can accomplish something big

Documents

More information © 2014 Denver Public Health The (frequently long, circuitous, and bumpy) trip from clinical problems to clinical trials Bill Burman Denver