* To assess the safety and tolerability of Ampligen administered intranasally in a dosing schedule for 13 days (7 doses) in healthy subjects.* To characterize the mucosal immune response following Ampligen administration over time.
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Frequency of local Treatment-Emergent Adverse Events (TEAEs)
* Frequency of systemic Treatment-Emergent Adverse Events (TEAEs)
* Frequency of any serious adverse events (SAEs)
* Frequency of any withdrawals due to Adverse Events (AEs)
* Frequency of any Dose Limiting Toxicities (DLTs)
* Change in laboratory values, vital signs, physical examination findings
(including nasal and oral examination)
* Nasal pain assessed by visual analogue scale (VAS)
* Integrity of the nasal mucosa by anterior rhinoscopy
* Levels of mucosal cytokines
* Characterization of mucosal immune cells
Secondary outcome
N.A.
Background summary
Ampligen®, a synthetic double-stranded RNA (Poly I: Poly C12U), is a
well-defined selective Toll-like receptor 3 (TLR3) agonist inducing innate
immune antiviral responses. TLR3 is expressed at high level in human airway
epithelial cells, including the nose and nasal pharynx. TLR3 serves as a
pathogen recognition receptor to stimulate the innate immune response against
many respiratory pathogens including coronaviruses (2). As a highly specific
TLR3 agonist, Ampligen stimulates the production of type I interferons, which
exert both antiviral and immunomodulatory activity. Besides activating TLR3,
Ampligen modulates the 2', 5' oligoadenylate synthetase/RNase L system and p68
protein kinase, which are both important natural antiviral pathways.
Ampligen has been administered intravenously in approximately 100,000 doses in
clinical trials (predominantly in the field of oncology) and compassionate use
programs (myalgic encephalomyelitis/chronic fatigue syndrome). Intranasal
administration of Ampligen as an universal flu adjuvant in combination with an
intranasal flu vaccine (Flumist®) was found to be well tolerated up to doses of
1250 *g (maximum proposed dose in this trial) administered thrice with an
interval of four weeks.
The route of human infection of SARS-CoV-2 is believed to be primarily by entry
into the nasal epithelium. Ampligen has been shown to inhibit the replication
of a wide variety of viruses in vitro and in vivo. Studies with the genetically
similar SARS-CoV in mice showed a significant protective effect of Ampligen,
coinciding with a significant decrease in pulmonary IL-6 levels. More recently,
in vitro antiviral activity against SARS-CoV-2 has been confirmed (unpublished
preclinical data). By dosing Ampligen every other day intranasally, it is
believed that SARS-CoV-2 can be inhibited at the point of entry, and thus will
be much less likely to progress to a pulmonary infection, or moderate COVID-19
disease. These characteristics make Ampligen a potent candidate to be developed
for an early treatment strategy and (post-exposure) prophylaxis against
COVID-19. Because Ampligen does not act by binding to proteins or specific
nucleic acid sequences of viruses it can also be developed for potential future
outbreaks with pathogenic coronavisurses (CoVs), or even other respiratory
viruses.
This phase I trial will assess the safety, tolerability and biological activity
of repeated administration of Ampligen intranasally every other day for 13 days
(7 doses) in healthy volunteers. This study is necessary for the further
development of Ampligen as a potential treatment modality for COVID-19 and
other pulmonary viral diseases.
Study objective
* To assess the safety and tolerability of Ampligen administered intranasally
in a dosing schedule for 13 days (7 doses) in healthy subjects.
* To characterize the mucosal immune response following Ampligen administration
over time.
Study design
This is a, randomized, double-blind, placebo-controlled, repeated dose study
performed in healthy adults.
Intervention
Ampligen will be administered intranasally via a nasal sprayer. An amount of
250 *L will be administered in each nostril (total volume of 500 *L per dose).
Each individual will receive the same dose throughout the treatment period.
Subjects will receive a total of 7 doses of Ampligen or placebo. Dosing will be
started on day 1 and will be administered every other day until day 13. A
starting dose of 75 *g will be used in the first cohort. Doses will be
escalated to 200 *g, 500 *g and a maximum dose of 1250 *g in the respective
following cohorts using a dose escalation design.
A placebo (normal saline) will be used as comparator in this study. The placebo
will be indistinguishable from the active compound.
Study burden and risks
Study participants will not have health benefit from study participation. Study
participants will not be protected from the coronavirus, COVID-19 or any other
respiratory infection. This clinical study will be important to support further
clinical evaluation of Ampligen as prophylactic or therapeutic modality to
fight COVID-19. The study will not only generate data on the
safety/tolerability of intranasal Ampligen administration, but also provide
insight into the proximal pharmacological activities of the compound, and
potential dose- and time-dependent effects. This information is critical for
rational dose selection for future clinical trials in COVID-19, or other
pulmonary viral diseases.
Participating in this study will take aproximatly 2 months, and a total of 13
visits. Subjects will have a medical screening (1 hour), a basline visit (1
hour), 2 long visits (8 hours), 8 short visits (1.5 hours) and a follow up
visit (1 hour). During the study, subjects will receive 7 doses of the
investigational compound or placebo spread over 14 days.
The following actions will be performed during these visits:
- Physical examination
- Questions about adverse events
- ECG
- Blood examination. The total blood that will be drawn during this study is 50
mL.
- Questionaire about nasal complaints after dosing
- Nose and throat swab to test for the presence of a SARS-CoV-2 infection or
any other respiratory infection.
- Nasal scrape to study the immune cells in the nose
- Nasal fluid will be taken by holding a small cotton swab in the nose for 1
minute
The possible side effects of the Ampligen are:
- Runny nose
- Headache
- Stuffy nose
- Sore throat
- Cough
- Fatigue
- Muscle strain
- Sinus pain
2117 SW Highway 484
Ocala, Florida 34473
US
2117 SW Highway 484
Ocala, Florida 34473
US
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure;
2. Male or female subjects, 18 to 70 years of age, inclusive at screening;
3. Body mass index (BMI) between 18 and 32 kg/m2, inclusive at screening, and
with a minimum weight of 50 kg.
4. Participant must be healthy, in the investigator*s clinical judgment, as
confirmed by medical history, physical examination, vital signs, ECG and
laboratory assessments performed at screening. Repeated laboratory testing may
be performed at the discretion of the clinical investigators for spurious
results on a case by case basis;
5. Willing to comply with effective contraception during the study if subject
is male or women of child bearing potential, up to 90 days after the last dose
of study treatment.
6. Has the ability to communicate well with the investigator in the Dutch
language and willing to comply with the study restrictions
Exclusion criteria
1. Evidence of any active or chronic disease or condition that could interfere
with, or for which the treatment of might interfere with, the conduct of the
study, or that would pose an unacceptable risk to the subject in the opinion of
the investigator (following a detailed medical history, physical examination,
vital signs (systolic and diastolic blood pressure, pulse rate, body
temperature) and 12-lead electrocardiogram (ECG). Minor deviations from the
normal range may be accepted, if judged by the Investigator to have no clinical
relevance;
2. Clinically significant abnormalities, as judged by the investigator, in
laboratory test results (including hepatic and renal panels, complete blood
count, chemistry panel and urinalysis. In the case of uncertain or questionable
results, tests performed during screening may be repeated before randomization
to confirm eligibility or judged to be clinically irrelevant for healthy
subjects;
3. Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV ab),
or human immunodeficiency virus antibody (HIV ab) at screening;
4. Respiratory tract infection (including flu and common cold symptoms) or any
febrile illness (>38°celsius) in the period of 3 days before first treatment
administration;
5. Presence of respiratory viral infection as determined by respiratory panel
on nasal swab at baseline (including positive SARS-CoV-2 PCR test);
6. History of chronic respiratory diseases (e.g. chronic obstructive pulmonary
disease, emphysema, chronic rhinitis or sinusitis, asthma or other reactive
airway diseases) in adulthood. Childhood asthma and non-active allergic
rhinitis (including hay fever) will be permitted at the discretion of the
investigator;
7. History of frequent nose bleeds;
8. Significant anatomical nasal abnormalities or other nasal abnormalities that
might impact the study executions (including, but not limited to, nasal septal
defects, cleft palate, nasal polyps, previous nasal cautery or surgery that
impacts study assessments);
9. Immunocompromised (known or expected immune deficiency, disease, or use of
medication that may affect the immune system) or evidence of autoimmune
disorder (deemed clinically relevant by the investigator);
10. Participation in an investigational drug or device study (last dosing of
previous study was within 90 days or 5 half-lives prior to first dosing of this
study);
11. History of abuse of addictive substances (alcohol, illegal substances) or
current use of more than 21 units of alcohol per week, drug abuse, or regular
user of sedatives, hypnotics, tranquillisers, or any other addictive agent;
12. Positive test for drugs of abuse at screening or pre-dose. Drugs test may
be repeated;
13. A routine smoker of tobacco products, currently or in the past year. No
(incidental) smoking will be allowed in the two weeks prior to first dosing;
14. Use of immunomodulatory drug; including systemic corticosteroids as well as
nasal preparations within 30 days before first dosing. Low dose topical use of
corticosteroids will be permitted. Other exceptions will only be made if the
rationale is clearly documented by the investigator;
15. Receipt of any vaccine within 1 week prior to IMP administration, or
planning to get vaccinated during the study;
16. Therapy with interferons, interleukins, or other cytokines within 6 weeks
of first dosing;
17. Known hypersensitivity to Ampligen or its excipients;
18. If a woman, pregnant, or breast feeding, or planning to become pregnant
during the study;
19. Any known factor, condition, or disease that might interfere with treatment
compliance, study conduct or interpretation of the results such as drug or
alcohol dependence or psychiatric disease.
20. History of Bell*s Palsy or other forms of facial paralysis.
21. Loss or donation of blood over 500 mL within three months (males) or four
months (females) prior to screening, or donation of plasma within 14 days of
screening or intention to donate blood or blood products during the study
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005898-26-NL |
| CCMO | NL76226.058.21 |