Clinical Trials Register

Summary
EudraCT Number:	2022-002827-36
Sponsor's Protocol Code Number:	C4671042
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-10-20
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2022-002827-36

A.3

Full title of the trial

AN INTERVENTIONAL, EFFICACY AND SAFETY, PHASE 2, RANDOMIZED, DOUBLE-BLIND, 2-ARM STUDY TO INVESTIGATE A REPEAT 5-DAY COURSE OF NIRMATRELVIR/RITONAVIR COMPARED TO PLACEBO/RITONAVIR IN PARTICIPANTS AT LEAST 12 YEARS OF AGE WITH REBOUND OF COVID-19 SYMPTOMS AND RAPID ANTIGEN TEST POSITIVITY

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Study to Learn About a Repeat 5-Day Treatment with Nirmatrelvir/Ritonavir in People with Return of COVID-19 Symptoms and SARS-CoV-2 Positivity After Finishing Treatment with Nirmatrelvir/Ritonavir

A.4.1

Sponsor's protocol code number

C4671042

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pfizer Inc.
B.5.2	Functional name of contact point	Clinical Trials.gov Call Centre
B.5.3	Address:
B.5.3.1	Street Address	66 Hudson Boulevard East
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	10001
B.5.3.4	Country	United States
B.5.4	Telephone number	+18007181021
B.5.6	E-mail	ClinicalTrials.gov_Inquiries@pfizer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	RITONAVIR
D.2.1.1.2	Name of the Marketing Authorisation holder	Camber Pharmaceuticals, Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ritonavir
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ritonavir
D.3.9.1	CAS number	155213-67-5
D.3.9.4	EV Substance Code	SUB10342MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Nirmatrelvir
D.3.2	Product code	PF-07321332
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Nirmatrelvir
D.3.9.3	Other descriptive name	Nirmatrelvir
D.3.9.4	EV Substance Code	SUB220919
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

SARS-CoV-2 Infection

E.1.1.1

Medical condition in easily understood language

COVID-19

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.1
E.1.2	Level	PT
E.1.2	Classification code	10084460
E.1.2	Term	COVID-19 treatment
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on viral RNA level in NP swabs in participants with mild-to-moderate COVID-19.

E.2.2

Secondary objectives of the trial

- To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on the duration of viral shedding.
- To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on the duration and severity of signs and symptoms in participants with mild-to-moderate COVID-19.
- To describe the safety and
tolerability of nirmatrelvir/ritonavir in participants with mild-to-moderate COVID-19.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Participants aged 12 years or older and weighing ≥40 kg at screening.
2. Participants must have written documentation with patient-reported 100% compliance (ie, completed a 5 day course of nirmatrelvir/ritonavir). They must have symptom alleviation or resolution in COVID-19 signs/symptoms followed by a worsening (rebound) of signs/symptoms after completing an initial 5-day course of nirmatrelvir/ritonavir based on the judgement of both the participant and investigator.
3. The onset of rebound in COVID-19 symptoms must occur within 2 weeks (14 days) after the completion of the initial 5-day course of nirmatrelvir/ritonavir.
4. Onset of rebound in signs/symptoms attributable to COVID-19 within 48 hours prior to randomization and ≥1 sign/symptom attributable to COVID-19 present on the day of randomization.
5. SARS-CoV-2 infection as determined by rapid antigen testing in any specimen collected within 24 hours prior to randomization and collected within 2 weeks (14 days) after the completion of the initial 5-day treatment course of nirmatrelvir/ritonavir.
6. Has at least 1 characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19.

E.4

Principal exclusion criteria

1. Current need for hospitalization, hospitalized for the index COVID-19 infection, or
anticipated need for hospitalization within 24h after randomization in the clinical
opinion of the site investigator.
2. History of severe chronic liver disease (eg, jaundice, ascites, hepatic encephalopathy, history of bleeding esophageal or gastric varices). No laboratory testing is needed.
3. History of hypersensitivity or other contraindication to any of the components of the study interventions, as determined by the investigator.
4. Suspected or confirmed concurrent active systemic infection other than COVID-19 that may interfere with the evaluation of response to the study intervention.
5. Receiving dialysis or eGFR <30 mL/min/1.73m2 (for adults) or eCrCl <30 mL/min (for adolescents) at screening using creatinine point of care device.
6. Oxygen saturation of <92% on room air obtained at rest within 24 hours prior to randomization.
7. Immunocompromised.
8. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
9. Current use of any prohibited concomitant medication(s).
10. COVID-19 vaccination within 14 days prior to study entry or anticipated COVID-19 vaccination through Day 34.
11. Receiving other COVID-19 specific treatments within 30 days of randomization and through Day 34, excluding the initial course of nirmatrelvir/ritonavir as well as blinded study medication.
12. Prior participation in this trial.
13. Current or previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).
14. Females who are pregnant up to 14 weeks gestation. Pregnancy ≥14 weeks is not exclusionary.
15. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.

E.5 End points

E.5.1

Primary end point(s)

The difference in mean change of SARS-CoV-2 RNA level in NP swabs from baseline to Day 5 between nirmatrelvir/ritonavir and placebo/ritonavir group in participants with a rebound in COVID-19
symptoms and a positive rapid antigen test within 2 weeks following completion of an initial 5- day treatment course ,who have a positive rapid antigen test result at baseline. This will be estimated without regard to study treatment discontinuation and without regard to prohibited therapies.

E.5.1.1

Timepoint(s) of evaluation of this end point

The difference in mean change of SARS-CoV-2 RNA level in NP swabs from baseline to Day 5 between nirmatrelvir/ritonavir and placebo/ritonavir group in patients with a rebound in COVID-19 symptoms and a positive rapid antigen test within 2 weeks following completion of an initial 5-day treatment course, who have a positive viral RNA NP swab test result at baseline. This will be estimated without regard to study treatment discontinuation and without regard to prohibited therapies.

E.5.2

Secondary end point(s)

- Time to 2 consecutive negative rapid antigen test results obtained at least 24 (-2) h apart through Day 28.
- Time (days) to sustained alleviation of all targeted signs and symptoms through Day 28 where sustained alleviation is defined as the first of 2 consecutive days when any symptoms scored as moderate or severe at baseline are scored as mild or absent and any symptoms scored as mild or absent at baseline are scored as absent.
- Incidence of TEAEs. Incidence of SAEs and AEs leading to discontinuation.

E.5.2.1

Timepoint(s) of evaluation of this end point

results obtained at least 24 (-2) h apart through Day 28 between nirmatrelvir/ritonavir and placebo/ritonavir group in patients with rebound in COVID-19 symptoms and a positive rapid antigen test within 2 weeks following completion of an initial 5-day treatment course, who have a positive viral RNA NP swab test result at baseline. This will be estimated without regard to study treatment discontinuation and without regard to prohibited therapies.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Taiwan

Canada

Germany

Greece

Italy

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

351

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

411

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

No study intervention will be provided to participants at the end of their study participation. It is expected that participants will be treated as required with standard-of-care treatments, as advised by their usual care physician.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2023-02-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-11-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-02-09

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