Clinical Trials Register

Summary
EudraCT Number:	2020-002295-13
Sponsor's Protocol Code Number:	APHP200552
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-05-22
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

France - ANSM

A.2

EudraCT number

2020-002295-13

A.3

Full title of the trial

Evaluation of the efficacy, safety and tolerability of alisporivir for the treatment of hospitalised patients with infections due to SARS-CoV-2 (COVID-19).
A randomised, open-label, proof of concept, Phase 2 study.

Evaluation de l’efficacité, la sécurité et la tolérance de l'alisporivir chez des patients hospitalisés pour une infection par le SARS- CoV-2 (COVID-19).
Étude de faisabilité de phase 2, randomisée, en ouvert.

A.3.1

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

Evaluation of the efficacy, safety and tolerability of alisporivir for the treatment of hospitalised patients with infections due to SARS-CoV-2 (COVID-19).

Evaluation l’efficacité, la sécurité et la tolérance de l'alisporivir chez des patients hospitalisés pour une infection par le SARS- CoV-2 (COVID-19).

A.3.2

Name or abbreviated title of the trial where available

CYCLOVID

A.4.1

Sponsor's protocol code number

APHP200552

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	Assistance Publique - Hôpitaux Paris
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DEBIOPHARM SA
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Assistance Publique - Hôpitaux Paris
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	1, av Claude Vellefaux
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	+330144841747
B.5.5	Fax number	+330144841701
B.5.6	E-mail	candy.estevez@aphp.fr

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	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	alisporivir
D.3.2	Product code	ALV, DEB025
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Nasogastric use (Noncurrent) Oral use
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The study population will consist of adults (18-80 years old) hospitalised for ≤48 hours prior to randomisation with a diagnosis of COVID-19 based on symptoms onset and SARS-CoV-2 RT-PCR test positive from nasopharyngeal swab. Patients with ARDS or patients requiring mechanical ventilation at screening or randomisation will be excluded

E.1.1.1

Medical condition in easily understood language

Adults hospitalised with a diagnosis of 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	23.0
E.1.2	Level	PT
E.1.2	Classification code	10051905
E.1.2	Term	Coronavirus infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to evaluate the reduction in SARS-CoV-2 viral load in nasopharyngeal swabs at D7 in patients hospitalised for COVID19 and treated either with alisporivir and SOC or SOC alone.

E.2.2

Secondary objectives of the trial

The secondary objective is to evaluate the clinical and radiological efficacy, safety and tolerability of alisporivir plus SOC compared to SOC alone in patients with COVID-19.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult males and females ≥18 years and ≤80 years of age at the time of screening.
2. Are hospitalised during the screening period with duration of hospitalisation prior to randomisation ≤48 hours.
3. Have a diagnosis of COVID-19 based on symptoms onset and SARS-CoV-2 RT-PCR test positive from nasopharyngeal swab.
4. Have at least one (1) of the following:
a. Radiographic pulmonary infiltrates (CT scan), AND/OR
b. Clinical assessment (evidence of rales/crackles on exam) AND SpO2 ≤94% on room air, AND/OR
c. Requirement of supplemental oxygen.
5. If female, of non-childbearing potential (e.g. post-menopausal as demonstrated by FSH or surgical sterilization i.e., tubal ligation or hysterectomy), or if of childbearing potential, be willing to commit to either sexual abstinence or use of at least 2 medically accepted, effective methods of birth control (e.g., condom, spermicidal gel, oral contraceptive, indwelling intrauterine device, hormonal implant/patch, injections, approved cervical ring) from screening through 7 months after last alisporivir dose.
6. If male, a willingness to refrain from donating sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, a willingness to use a condom in addition to having the female partner use a highly effective method of birth control (such as an intrauterine device, diaphragm, oral contraceptives, injectable progesterone, subdermal implants, or a tubal ligation) from screening through 4 months after last alisporivir dose.
7. Willing and able to provide written informed consent.
8. Willing to comply with all study assessments and adhere to the protocol schedule.
9. Has an affiliation with a social security system.

E.4

Principal exclusion criteria

1. Patients with ARDS or patients requiring mechanical ventilation at screening or randomisation.
2. In the opinion of the investigator, the patient is unlikely to survive the following 7 days after randomisation due to a rapidly progressive or terminal illness with a high risk of mortality due to any cause, including acute hepatic failure, respiratory failure or severe septic shock.
3. Patients who are unconscious or considered by the investigator unable to consent.
4. Other severe co-morbidity with life expectancy ≤3 months according to the investigator’s assessment.
5. Critically ill patients who have an APACHE II score ≥30.
6. Concomitant severe bacterial infection including blood stream infections, endocarditis, osteomyelitis, retroperitoneal abscess, septic arthritis, or meningitis diagnosed within 7 days prior to randomisation (bacterial pulmonary infection that may complicate COVID-19 is not an exclusion criterion).
7. Any of the following signs of severe sepsis:
a. Shock or profound hypotension defined as systolic blood pressure ≤90 mm Hg or a decrease of ≥40 mm Hg from the value obtained during screening (if more than one measurement is taken) that is not responsive to fluid challenge.
b. Hypothermia (core temperature ≤ 35.6°C).
c. DIC as evidenced by PT, PTT 2 × ULN, or platelets ≤ 50% of the LLN.
8. History of positive test for HIV including all patients currently on HAART regardless of the CD4+ cell count.
9. Presence of immunodeficiency or an immunocompromised condition including neutropenia (≤1,000 neutrophils/mm3 obtained from the local laboratory at screening), haematologic malignancy, history of haematopoietic stem cell transplant, history of solid organ transplant, receiving immunosuppressive therapy (e.g. cancer chemotherapy, mAbs for autoimmune disease, or medications to prevent transplant rejection), and long term use of systemic corticosteroids (e.g., ≥20 mg/day of prednisone or systemic equivalent for at least 2 weeks).
10. Severe hepatic impairment at screening, as evidenced by ALT or AST ≥3 × ULN or total bilirubin ≥2 × ULN (except in case of known Gilbert syndrome), or clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, hepatic encephalopathy).
11. Acute hepatitis, cirrhosis (any Child-Pugh class), acute hepatic failure or acute decompensation of chronic hepatic failure.
12. Alkaline phosphatase ≥3.0 × ULN. Patients with values ≥3.0 × ULN and ≤5.0 × ULN are eligible if this value is documented to be acute and directly related to the infectious process being treated.
13. Severe renal impairment (creatinine-clearance ≤30 mL/min) or ESRD requiring haemodialysis or peritoneal dialysis, according to Cockcroft-Gault.
14. Uncontrolled hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg).
15. Uncontrolled thyroid function (TSH, free T3 or free T4 outside of normal ranges).
16. History of known or suspected Clostridium difficile infection.
17. History of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures).
18. Acute co-morbidity within 7 days before inclusion such as myocardial infarction.
19. A female who is pregnant or breastfeeding.
20. Documented hypersensitivity reaction or anaphylaxis to alisporivir, one of the non-active ingredients or any of the SOC medications.
21. Receipt of any investigational medication in the 3 months prior to screening.
22. Anticipated transfer to another hospital that is not a study site during the first 4 days of treatment.
23. Patients previously treated with antivirals, immunomodulators (mAbs in the 3 months prior to screening) and other medicines prohibited in this study (see Section 18.7) in the 14 days prior to randomisation.
24. Ongoing or recent use of any other medication (including over the counter medication and herbal products) within 14 days before randomisation or within 5 drug half-lives of that medication (whichever is longer) that are known inhibitors/inducers of cytochrome P450 3A or P-gp, or inhibitors of OATPs, MRP2 or BSEP (see Section 18.7). Known need of concomitant treatment with the following medications during treatment with alisporivir and 14 days after the end of treatment:
a. Known inhibitors/inducers of cytochrome P450 3A or P-gp, or inhibitors of OATPs, MRP2 or BSEP;
b. Drugs with narrow therapeutic index that are known sensitive substrates of cytochrome P450 3A, or substrates of P-gp, OATPs, MRP2 or BSEP.
25. Any other condition or prior therapy, which, in the opinion of the investigator, would make the patient unsuitable for this study, including those that would prevent compliance with all study assessments and adherence to the protocol schedule.
26. Patients with history of pancreatic disease.
27. Patients under legal protection.
28. Prisoners.
29. Patients participating in another interventional study.

E.5 End points

E.5.1

Primary end point(s)

The endpoint of the primary objective "to evaluate the reduction in SARS-CoV-2 viral load in nasopharyngeal swabs at D7 in patients hospitalized for COVID-19 and treated either with alisporivir and SOC or SOC alone" is presented in Table 4 1. Viral load in cells taken from nasopharyngeal swabs will be measured using the RT-PCR COVID 19 test based on droplet digital PCR, a method allowing for normalization to the cell content in the sample.
Endpoint : VLRR, defined as the proportion of patients with an intra patient decrease of ≥ 1.5 log10 viral load, at D7 compared to Baseline

E.5.1.1

Timepoint(s) of evaluation of this end point

Timeframe/Time Point : D1 directly after randomisation (for Arm 1 before the first alisporivir administration) and D7

E.5.2

Secondary end point(s)

Percentages of patients negative for SARS CoV 2 RNA in nasopharyngeal swabs at D14 (EOT) and FUP visits in the two treatment arms.
Time to negative viral load
Time to resolution of symptoms
Duration of need for supplemental oxygen
Duration of hospitalisation - measured in days.
Duration of new non-invasive ventilation or high flow oxygen use
Duration of new oxygen use
Duration of new ventilator or ECMO use
Number of non-invasive ventilation/high flow oxygen free days
Number of oxygenation free days
Patient all-cause mortality at D14 (EOT visit), at D28 (FUP14), at D90 (EOS): Date and cause of death (if applicable).
Safety:
Cumulative incidence of any AE
Cumulative incidence of Grade 3 and 4 AEs
Cumulative incidence of SAEs

E.5.2.1

Timepoint(s) of evaluation of this end point

EOT, FUP7 and D28 ± 2 days
D1 to D28 ± 2 days
D1 to D28 ± 2 days and to D90± 2 days
D1 to D28 ± 2 days and to D90± 2 days
D1 to D28 ± 2 days and to D90± 2 days
D1 to D28 ± 2 days and to D90± 2 days
D1 to D28 ± 2 days and to D90± 2 days
D1 to D28 ± 2 days and to D90± 2 days
D1 to D28 ± 2 days and to D90± 2 days
D1 to D28 ± 2 days and to D90± 2 days
D1 to EOT, and to D28 ± 2 days, and to D90± 2 days
D1 to D90 ± 2 days
D1 to D90 ± 2 days
D1 to D90 ± 2 days

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

SOC

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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 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:

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

100

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)

None

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

2020-10-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-26

P. End of Trial
P.	End of Trial Status	Ongoing

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