Primary Objective - To determine if afamelanotide can reduce the severity of PLE related pruritis.Secondary Objectives- To determine if afamelanotide can reduce the frequency of PLE episodes;- To determine if afamelanotide can reduce the duration of…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Immune disorders NEC
- Skin and subcutaneous tissue disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To determine if afamelanotide can reduce the severity of PLE related
pruritis.
Secondary outcome
- To determine if afamelanotide can reduce the frequency of PLE episodes;
- To determine if afamelanotide can reduce the duration of PLE episodes;
- To evaluate the effect of afamelanotide on the use of rescue medication for
the treatment of PLE episodes;
- To evaluate the effect of afamelanotide on the quality of life of PLE
patients; and
- To evaluate the safety and tolerability of afamelanotide by measuring
treatment-emergent adverse events.
Background summary
When human skin is exposed to ultraviolet radiation from the sun or via the use
of solaria, it responds by increasing melanin levels within epidermal
melanocytes. Ultraviolet light is thought to enhance the local production and
release of alpha-melanocyte stimulating hormone (alpha-MSH), which results in
increased melanin levels through a process known as melanogenesis. Melanin, in
the form of eumelanin, is a photoprotective agent. The mechanisms proposed for
photoprotection include, but are not limited to, the absorption and scattering
of UV light, free radical scavenging and quenching of UV light. There is also
increasing evidence that melanogenesis represents a major antioxidant defence
mechanism in melanocytes, neutralising the deleterious effects of free radicals
and active oxygen species. Eumelanin acts as a neutral density filter and,
unlike most sunscreens, reduces all wavelengths of light equally so that the
photoprotection provided by epidermal melanin pigmentation is essentially
independent of wavelength.
Afamelanotide ([Nle4-D-Phe7]-alpha-MSH) is a potent and longer lasting analogue
of alpha-MSH which stimulates the production of eumelanin in the skin without
the specific cell damage that usually occurs when melanin production is
stimulated by UV radiation. In several clinical studies, Afamelanotide has been
shown to stimulate eumelanin production and to have photoprotective properties:
following exposure to controlled amounts of UV radiation Afamelanotide was
assessed to render protection against damage to skin cells. In over 140
subjects, who were administered daily subcutaneous injections of afamelanotide
in saline (0.08 to 0.4 mg/kg/day for 10 days), significant increases in skin
eumelanin levels were observed. The use of afamelanotide as an aqueous
injection was associated with adverse reactions such as nausea, facial flushing
and gastrointestinal discomfort (81%, 74% and 22% of subjects respectively).
A more user-friendly sustained release implant formulation was developed to
reduce the incidence of adverse reactions. Implants containing 10 mg to 40 mg
of afamelanotide were found to stimulate eumelanin levels to a greater extent
than that seen with the aqueous injections. This increased pharmacological
activity was associated with a reduced incidence of adverse reactions. Nausea,
facial flushing and gastrointestinal discomfort were experienced by only 20%,
14% & 10% of subjects respectively and these adverse reactions were generally
mild in nature and usually lasted no more than one day.
PLE is a prevalent photosensitivity disorder of the skin, occurring in up to
20% of the European and US populations and up to 5% of the Australian
population. While the etiology is uncertain, exposure to sunlight in spring and
early summer is believed to be the primary factor initiating an outbreak of the
disease. There is currently a lack of effective treatments for PLE. The
mainstays of management of symptomatology are:
• sunscreens
• topical steroid creams
• *skin hardening* with controlled ultraviolet (UV) radiation.
Due to the carcinogenic potential of the UV-A/B desensitisation treatment, many
clinicians do not routinely use this but reserve it for patients with severe
cases or those with special needs.
Therefore, there is a need for alternative strategies to combat this syndrome
and afamelanotide appears to be a suitable candidate for prophylactic treatment.
In this phase III study, it is proposed to use implants containing 16 mg
afamelanotide as a photoprotective treatment for patients with Polymorphic
Light Eruption (PLE).
Study objective
Primary Objective
- To determine if afamelanotide can reduce the severity of PLE related
pruritis.
Secondary Objectives
- To determine if afamelanotide can reduce the frequency of PLE episodes;
- To determine if afamelanotide can reduce the duration of PLE episodes;
- To evaluate the effect of afamelanotide on the use of rescue medication for
the treatment of PLE episodes;
- To evaluate the effect of afamelanotide on the quality of life of PLE
patients; and
- To evaluate the safety and tolerability of afamelanotide by measuring
treatment-emergent adverse events.
Study design
Patients will be randomized to receive either active (afamelanotide) treatment
or placebo in a ratio of 2:1 and treated for a total period of 4 months using a
parallel design. Analysis of efficacy and safety will occur by pooling data
from the active treatment arm and comparing this with pooled data from the
placebo arm.
Pruritus will be used as a surrogate marker of the severity of PLE episodes.
The intensity of pruritus will be evaluated using an 11 point Likert scale:
(0 [no pruritus]-10 most severe pruritus]) via a paper patient diary. A
detailed questionnaire assessing various characteristics of pruritus will be
conducted at screening, Day 0, Day 60 and Day 120.
Intervention
Not applicable
Study burden and risks
(1) Prophylactic phototherapy will be withheld. Therefore there is a risk that
the patients may experience PLE when the summer commences. However, this
therapy is not routine for patients due to the inherent risks and the
cumulative increase in the risk of skin cancer.
(2) Adverse events (AEs) or risks associated with afamelanotide. The sustained
release implant alpha*MSH has been previously administered with mild AEs
occuring in 10*20% of subjects. These included nausea, facial flushing and
gastrointestinal discomfort experienced by 20%, 14% and 10% of subjects
respectively. These AEs were generally mild in nature and usually lasted no
more than 1 * 2 days. Other mild AEs which have been reported less commonly
include headache, chemical taste in the mouth, yawning, muscle twitching,
diarrhoea, light*headedness and nervousness. Irregular skin tanning, darkening
of moles and freckling are also reported. (NB: Darking of moles and freckling
are not strictly AEs as they represent the natural effects of the drug. Howevet
the rapidity of the change was such as to b recorded as an unexpected event).
(3) The active implant is a sterile biodegradable and biocompatible
poly(D,L*lactide*co*glycolide) polymer excipient containing 16 mg of
afamelanotide. The placebo implant is identical in composition except it does
not contain afamelanotide. The implants contain no other excipients. These
implants are manufactured by SurModics Pharmaceuticals, Birmingham, Alabama,
USA.
(4) Implant procedure * the main risk is discomfort and bruising at the site of
the implant. Less commonly seen side effects are infection, bleeding from the
incision site, fainting and nausea. Any patient who experiences any moderate or
severe toxocity (as judged from observed adverse events) considered related to
the drug may have the implant removed surgically otherwise the implant will
biodegrade over succeeding
2*3 months.
(5) Venepuncture * the main risk is discomfort and bruising at the site of
venepuncture/cannulation. Less commonly seen side effects are infection,
bleeding from the puncture site, fainting and nausea.
330 Collins Street
Melbourne VIC, 3000
AU
330 Collins Street
Melbourne VIC, 3000
AU
Listed location countries
Age
Inclusion criteria
- Aged greater than 18 years;
- Male or female patients with a documented history of PLE diagnosed or confirmed by a photodermatologist or photobiologist, with a history of PLE related pruritus symptoms;
- Recurrent PLE episodes that occur at least once a year (as evidenced by PLE related pruritus symptoms) developing in their own country (to exclude patients affected only when traveling to sunnier climates);
- Written informed consent prior to the performance of any study-specific procedure; and
- Are willing and able to comply with the conditions specified in this protocol and study procedures in the opinion of the Investigator.
Exclusion criteria
- Personal history of melanoma, lentigo maligna or multiple (3 or more) dysplastic nevi;
- Current Bowen*s Disease, basal cell carcinoma, squamous cell carcinoma or other malignant skin lesions;
- Patients currently requiring treatment with systemic immunosuppressive agents;
- Documented history of other photosensitive conditions which may be confused with PLE or interfere with the assessment of PLE episodes;
- Solarium use in the three months prior to study involvement and throughout the duration of the study;
- Use of immunosuppressive medications, drugs that cause hyperpigmentation or any other treatment that in the opinion of the investigator may interfere with this study;
- Documented presence (> 1 in 320) of Anti Nuclear Antibody (ANA) and/or positive Extractable Nuclear Antibody (ENA); historical results from the 3 years prior to randomisation are acceptable if available;
- In the opinion of the investigator, any evidence of clinically significant organ dysfunction, or any clinically significant deviation from normal in clinical or laboratory parameters;
- History of drug or alcohol abuse (in the last 1 year);
- Female who is pregnant (confirmed by positive serum β-HCG pregnancy test prior to baseline) or lactating;
- Females of child-bearing potential (pre-menopausal, not surgically sterile) that are not using or are not willing to use adequate contraceptive measures (e.g. oral contraceptives, condoms, diaphragm plus spermicide, intrauterine device);
- Sexually active men with partners of child bearing potential not willing to use barrier contraception during the trial and for a period of three months hereafter;
- Participation in a clinical trial with another IMP within 30 days prior to the screening visit or during the study;
- Hypersensitivity to afamelanotide or any of its components;
- Hyperpigmentary disorders; and
- Use of therapeutic doses of β-carotene and other excluded medicines, as described in the study protocol (in the last 3 months).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-017359-92-NL |
| CCMO | NL31059.078.10 |