Phase 2b placebo-controlled trial of M72/AS01E

candidate vaccine to prevent active tuberculosis

in adults

Olivier Van Der Meeren, MD,* Mark Hatherill, MD, FCPaed,* Videlis Nduba, MBChB, MPH, Robert J

Wilkinson, F Med Sci, Monde Muyoyeta, MBChB, PhD, Elana Van Brakel, MBChB, MSc, Helen M Ayles,

MBBS, PhD, German Henostroza, MD,§ Friedrich Thienemann, MD, Thomas J. Scriba, PhD, Andreas

Diacon, MD, PhD, Gretta L. Blatner, MS, MPH, Marie-Ange Demoitié, MSc, Michele Tameris, MBChB,

Mookho Malahleha, MD, MPH, James C. Innes, MBChB, MSc, Elizabeth Hellstrom, MBChB, MPhil, Neil

Martinson, MBChB, MPH, Tina Singh, MD, Elaine Jacqueline Akite, MSc, Aisha Khatoon, MBBS, Anne

Bollaerts, MSc, Ann M. Ginsberg, MD, PhD, Thomas G. Evans, MD,† Paul Gillard, MD,** and Dereck R.

Tait, MBChB, FRCPath**al

N Engl J Med. 2018 Sep 25

Hintergrund

Mycobacterium tuberculosis

• Leading infectious cause of death worldwide

• 2017: 10.000.000 fell ill, 1.600.000 died; estimated 558.000 MDR

• WHO aim: Reduce deaths by 95%, reduce new cases by 90%

until 2035

• Only licensed TB vaccine: BCG (bacille Calmette-Guérin)

Study

• M72/AS01E: recombinant fusion protein (Mtb32A + Mtb39A) +

Adjuvant (System AS01 Mosquirix, Shingrix)

• Prevention of acive pulmonary TB in HIV-negative adults with

latent TB (pos. IGRA)

• GlaxoSmithKline Biologicals

Study design / Methods

Multi-center, double-blind, randomized (1:1), placebo-controlled

• Kenya, South Africa, Zambia – 11 study sites

Follow up: for 3a

• Pre-specified primary analysis after 2 years

• Final analysis after 3 years planned.

Study design – Inclusion / Exclusion

Inclusion:

• Adults (18-50a), non-pregnant; pos. QFT

• Healthy/stable med. cond., HIV-neg.

• No TB-symptoms,, neg. sputum PCR (GeneXpert)

Vaccination:

• 2 doses of M72/AS01E or placebo deltoid, 1 month apart

Exclusion:

• >14d immunosuppressants/immune-modifying drugs within last 6 months (z.B.

≥20mg Prednison/d)

• Immunodeficient disorder; autoimmune disease

• Administration of Ig / Blood products within 3 months

Efficacy endpoints

Primary objective (primary endpoint)

• Vaccine efficacy* to prevent active pulmonary TB (case def. 1)

Secondary objectives (secondary endpoints)

• VE (additional case definitions: 2-5)

• Immunogenicity + safety of the vaccine.

• Immunogenicity (CMI response, humorale immune response

assessed in subgroup (300 Patients)

*VE = Vaccine efficiacy

Case definitions

Evaluation for TB

TB Surveillance

• Active (visits, calls, text) + passive (self reporting)

• Suspicion : 3x sputum over 1 week; PCR + culture (Case def. 3-5: up

to 4 weeks after start treatment)

• Diagnostic/treatment decisions by non-study physicians

• HIV-retest and screening for diabetes in all confirmed TB-cases

Evaluation for safety / Immunogenicity

Evaluation of safety

Whole cohort:

• Serious adverse events, potential immune-mediated diseases: recorded until

6 months after 2. dose

Related to study product: until end of study

• Unsolicited AE: until 30d after each dose

Sub-cohort (N=299)

• Solicited AE until 7d after each dose.

• Laboratory (Chem./hemat.): days 0, 7, 30, 37

Evaluation of immunogenicity of the subgroup

• Anti-M72IgG (ELISA) before dose 1 + 1 month post dose 2 + annually until

year 3

• M72-specific CD4+/CD8+ T-cells

Screening and Randomization 1/2

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Results – Primary analysis (after mean follow up 2.3y) - According-

to-protocol analysis (Start 30d after 2. dose)

N = 1623 N = 1660

N = 1785 N = 1783

Kaplan–Meier Estimate of Definite Pulmonary Tuberculosis (First Case

Definition) – According-to-protocol efficacy cohort

Vaccine Efficacy (Case Definition 1: Covariate)

Solicited:

(most frequently)

M72/ASO1E N=148 Placebo N = 151

Pain (81%) (34.4%)

Fatigue/malaise/

myalgia

(58.1-68.9%) (26.5-47%)

Fever (>38°C)

Fever (>39.5°C)

(18.9%)

(4.1%)

(6.6%)

(1.3%)

Immunogenicity: 100% seroconversion at month 2,

99% at month 12)

Discussion

Significant lower incidence of pulmonary Tb in M.

tuberculosis infected ,HIV-neg., healthy BCG-vacc. adults

Limitations:

• Possible active Tb while inclusion

• Only open pulmonary Tb for primary case definition

Differences in age and gender?

• Hypothesis : Less recent infection / infection under control

• Not enough power to detect differences between

subgroups

Vielen Dank für die Aufmerksamkeit!

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