Initiation of Symptomatic Medication in Alzheimer’s ... Initiation of Symptomatic Medication in Alzheimer’s Clinical Trials: Hypothetical vs Treatment Policy Approach Michael C

Initiation of Symptomatic Medication in Alzheimer’s Clinical Trials:

Hypothetical vs Treatment Policy Approach

Michael C Donohue1, Fabian Model2, Paul Delmar2, Nicola Volye2, Hong Liu-Seifert3, Michael S Rafii1, Paul S Aisen1

1. Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego

2. F. Hoffmann - La Roche Ltd, Basel, Switzerland

3. Eli Lilly, Indianapolis, Indiana

Background

ICH E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials (Aug 2017):• Sparked discussion of appropriate handling of intercurrent events,

such as initiation of concurrent medications in Alzheimer’s trials.• Treatment policy strategy: collect and analyze until end of planned

observation period, regardless of intercurrent events• Effectiveness, De Facto, Intention-to-treat

• Hypothetical strategy: The efficacy under some hypothetical scenario (e.g. in absence of an intercurrent event)• Efficacy, De Jure

Background

EMA Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease (Feb 2018):

“In general, and unless an alternative is duly justified, the actual adherence to treatment should be reflected in the target of estimation (i.e. the “treatment-policy” strategy should be applied for this intercurrent event).”

Examples of estimand definitionsIntercurrent event Approach Population Endpoint Population-level

summary

None NA Inc/Exc Criteria Change from baseline to month 6

Group diff. in means

Switching to rescue med.

Treatment policy Same Change from baseline to month 6

Group diff. in means regardless of event

Captured in composite outcome

Composite strategy Same Composite binary response and no switching

Group diff. in response proportions

Switching to rescue med.

Hypothetical strategy Same Change from baseline to month 6

Group diff. in means had rescue med. not been available

Committee for Human Medicinal Products. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials, Step 2b. In:2017.

Examples of estimand definitionsIntercurrent event Approach Population Endpoint Population-level

summary

Captured through population

Principal stratum strategy

Inc/ExcCriteria; would not require rescue

Change from baseline to month 6

Group diff. in means

Captured through variable

While on treatment strategy

Inc/ExcCriteria

Average response while on randomized treatment

Group diff. in means while on randomized treatment

Committee for Human Medicinal Products. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials, Step 2b. In:2017.

Concurrent Symptomatic Meds in MCI trials

• In Mild Cognitive Impairment (MCI) trials, it is common for participants to initiate concurrent symptomatic meds for Alzheimer’s post-randomization• Example: Phase 3 study of 799 prodromal Alzheimer’s patients

reported 46 (5.8%) patients had initiated an acetylcholinesterase inhibitor (AChEI) or memantine at the time of futility analysis1

• Had the study been completed, upwards of 10% might have initiated

• Some might hypothesize that a Treatment Policy approach to this intercurrent event would reduce the apparent experimental treatment effect relative to a Hypothetical approach.

Ostrowitzki S, Lasser RA, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease. Alzheimers Res Ther. 2017;9(1):95.

Effects of Donepezil2

Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379-397.

Effects of Galantamine2


Effects of Rivastigmine & Memantine2


Treatment policy concern

Time

Resp

onse

Placebo (Med-free observations)

Active

Placebo (All observations)

Therefore we might assume: E[Treatment policy effect] < E[Hypothetical effect | no symptomatic meds]Is this assumption supported by available data?

Schneider LS, Insel PS, Weiner MW. Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Archives of neurology. 2011;68(1):58-66.

Han JY, Besser LM, Xiong C, Kukull WA, Morris JC. Cholinesterase Inhibitors May Not Benefit Mild Cognitive Impairment and Mild Alzheimer Disease Dementia. Alzheimer Dis Assoc Disord. 2019;33(2):87-94.

N

On symptomatic medication at baseline

(N=351)

Initiated symptomatic medication

(N=147)

Never Initiated symptomatic medication(N=479)

Combined

(N=977)

P-value

eMCI at baseline 977 74 (21%) 41 (28%) 240 (50%) 355 (36%) <0.001Age (years) 977 73.2 (7.18) 74.2 (6.98) 72.4 (8.12) 72.9 (7.65) 0.015Sex (female) 977 129 (37%) 58 (39%) 214 (45%) 401 (41%) 0.066Education (years) 977 15.9 (2.81) 15.8 (2.82) 16.0 (2.80) 16.0 (2.80) 0.607APOEe4 alleles 603 <0.0010 136 (41%) 62 (42%) 272 (60%) 470 (50%)1 147 (44%) 67 (46%) 151 (33%) 365 (39%)2 52 (16%) 18 (12%) 32 (7%) 102 (11%)

CSF Ab1-42 (pg/ml) 619 796 (372) 799 (375) 1145 (431) 961 (437) <0.001Florbetapir PET (SUVR) 488 1.31 (0.24) 1.30 (0.22) 1.15 (0.20) 1.22 (0.23) <0.001Amyloid positive 743 154 (59%) 75 (64%) 204 (56%) 433 (58%) 0.300CDR Sum of Boxes 977 1.822 (0.944) 1.561 (0.817) 1.261 (0.768) 1.508 (0.880) <0.001ADAS-Cog 13 970 19.60 (6.47) 18.93 (6.19) 14.11 (5.98) 16.80 (6.73) <0.001MMSE 977 27.15 (1.84) 27.33 (1.80) 28.03 (1.71) 27.61 (1.82) <0.001Hippocampus (/ICVx1,000) 744 4.179 (0.736) 4.164 (0.746) 4.738 (0.772) 4.444 (0.805) <0.001Follow-up (years) 977 3.42 (2.68) 4.85 (2.15) 3.45 (2.94) 3.65 (2.78) <0.001Exposure to symptomatic meds (years) 977 - 2.913 (1.803) - - -

Table 1. Characteristics of ADNI MCI participants grouped by whether or not the participant initiated a symptomatic medication during the course of follow-up. P-values are from Pearson’s c2 test or Kruskal-Wallis test.

ADNI MCI characteristics

Cognitive worsening not “reversed” by sympt. medsADAS13

CDRSBM

MSE

−5 0 5 10

0

20

40

60

0

5

10

15

10

20

30

Years since initiation of symptomatic medication

ADAS13C

DR

SBM

MSE

−5 0 5 10

0

20

40

60

0

5

10

15

10

20

30

Years since initiation of symptomatic medication

0

20

40

60

−5 0 5 10

ADAS

13

0

5

10

15

−5 0 5 10

CD

RSB

10

20

30

−5 0 5 10Years since initiation of symptomatic medication

MM

SE

MMRM analysis

Mixed Model of Repeated Measures (MMRM) analysis of ADAS-Cog (13 item), CDRSB, MMSE change from baseline.• Categorical time• Covariates: baseline score, APOEe4 carriage, and age• Two datasets:

1. Treatment policy: All available observations2. Hypothetical: Exclude all observations after initiation of symptomatic meds

Including post-rescue data leads to worse trends

0

5

10

15

0 12 24 36 48 60 72 84 96 108 120 132Month

ADAS

13

All observationsMed−free observations

508483

433351

376297

281204

178129

143100

8961

5538

2519

1915

1010


0

1

2

3

4

50 12 24 36 48 60 72 84 96 108 120 132

Month

CD

RSB

503478

432347

374293

280202

177128

143100

9263

5539

2619

1915

1110


−4

−2

0

0 12 24 36 48 60 72 84 96 108 120 132Month

MM

SE

510485

440355

381299

286208

180131

146103

9465

5740

2921

1915

1110


Similar trend for Prodromal (Ab+) MCI

0

10

20

300 12 24 36 48 60 72 84 96 108 120 132

Month

ADAS

13


251237

223185

202162

163120

10778

7953

5434

3120

118

97

44


0.0

2.5

5.0

7.5

0 12 24 36 48 60 72 84 96 108 120 132Month

CD

RSB

247233

220180

200160

163120

10778

8054

5736

3019

127

97

44


−7.5

−5.0

−2.5

0.0

0 12 24 36 48 60 72 84 96 108 120 132Month

MM

SE

251237

226186

203162

165122

10980

8054

5837

3120

149

97

44


First 36 months

0

1

2

3

0 6 12 18 24 36Month

ADAS

13


512507

508483

176149

433351

376297


0.00

0.25

0.50

0.75

1.00

1.250 6 12 18 24 36

Month

CD

RSB

511506

503478

173146

432347

374293


−1.5

−1.0

−0.5

0.0

0 6 12 18 24 36Month

MM

SE

515510

510485

177150

440355

381299


Treatment policy concern revisited

Time

Resp

onse


Active

Placebo (All available data)

ADNI data suggests E[Treatment policy effect] > E[Hypothetical effect | no symptomatic meds]

The selection bias induced by requiring rescue is stronger than the benefit of symptomatic treatment

Discussion points

• ADNI may not be representative of every clinical trial (higher levels of education and more symptomatic medication use)• Still, departing from treatment policy approach is not supported

• By excluding observations, are we actually estimating:• Hypothetical effect had rescue not been available?• Or something closer to “while on randomized treatment” (alone)?

• Potential application of a delta method approach in which we perturb post-rescue observations to have more decline?

Is excluding observations providing the correct estimate of hypothetical estimand?

Time

Resp

onse


Active

Placebo (All available data)

Placebo (Had rescue notbeen available)

Recommendations

• Use treatment policy approach for initiation of symptomatic meds• Equivalently, we might conclude initiation of approved symptomatic

meds need not be considered an important intercurrent event.

Documents

Initiation of Symptomatic Medication in Alzheimer’s ... Initiation of Symptomatic Medication in Alzheimer’s Clinical Trials: Hypothetical vs Treatment Policy Approach Michael C