The primary objective of this study is to determine the clinical efficacy of doxycycline and metformin compared with the standard treatment with doxycycline alone after 24 weeks of treatment.
ID
Source
Brief title
Condition
- Skin appendage conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the difference in International Hidradenitis
Suppurativa Severity Score System (IHS4) between the groups at week 24.
Secondary outcome
Patient reported outcome measures:
• Change in skin related pain on a numerical rating scale from baseline and
differences between the groups at week 12 and 24.
• Change in self-reported frequency of flares from baseline and differences
between the groups at week 12 and 24.
• Change in quality of life measures with the DLQI and EQ-5D-5L from baseline
and differences between the groups at week 12 and 24.
• Treatment satisfaction and recommendation on a 5- and 3-point Likert scale
respectively after 12 and 24 weeks
Clinical efficacy
• Change in lesion count from baseline and differences between the groups at
week 12 and 24.
• The percentage of HiSCR achievers after 12 and 24 weeks
• The percentage of modified HiSCR achievers after 12 and 24 weeks
• The percentage of patients with a reduction in HS-PGA from baseline and
differences between the groups at week 12 and 24. after 12 and 24
weeks
Insulin resistance and metabolic syndrome
• Change in insulin resistance measured with the HOMA-IR from baseline and
differences between the groups at week 12 and 24.
• Change in HbA1c after from baseline and differences between the groups at
week 12 and 24.
• Change in parameters of metabolic syndrome (waist circumference, blood
pressure, HDL cholesterol, and triglycerides) from baseline and
differences between the groups at week 12 and 24.
Cost-effectiveness
• Cost-effectiveness of both treatments
Biomarker:
• The correlation between baseline calprotectin levels and baseline disease
severity.
• The correlation between calprotectin levels and treatment response at week 12
and 24.
Safety and tolerability:
• Incidence and severity of all adverse events throughout the study
Background summary
Hidradenitis suppurativa (HS) is a chronic, immune-mediated inflammatory skin
disease characterised by painful inflammatory nodules and abscesses. Risk
factors are female gender, a family history of HS, smoking, and overweight or
obesity. The latter factors together with the high inflammatory load in HS lead
to a high concomitant disease burden of metabolic syndrome and (pre)diabetes. A
meta-analysis showed an odds ratio of 2.85 for diabetes (95%CI 1.34-6.08) and
an odds ratio of 2.22 for metabolic syndrome (95%CI 1·62-3.06) in patients with
HS compared with healthy controls.
Current guidelines for the treatment of this debilitating disease recommend
treatment cycles with antibiotics with anti-inflammatory properties.However,
patients often suffer from gastro-intestinal side effects and yeast infections,
and rightfully worry about antibiotic resistance. Based on the pathogenesis of
HS other systemic treatments with anti-inflammatory properties are potential
candidates to alleviate HS symptoms, indicating that we should broaden our
scope beyond antibiotics.
In the past years the evidence for the immunomodulatory properties of metformin
has been mounting. A growing body of evidence suggests that metformin affects
key immunological functions of T- and B-lymphocytes, and macrophages, cells
implicated in HS pathogenesis.
This provides a strong rationale for the treatment of HS with metformin. An
open label, pilot study with metformin has been performed in HS.21 In this
study 18 out of 25 patients noticed a clinically meaningful improvement with an
average reduction in Sartorius score of 7.6 points (SD 11.2) after 12 weeks of
treatment, with an additional reduction of 5.1 points after prolonged
treatment, reaching a total reduction of 12.8 points (SD 11.3) after 24 weeks.
Minimal side effects were noted. A recent retrospective study (n=53) showed
that metformin could be given for prolonged periods of time while being well
tolerated. This study also highlighted the high prevalence of (pre-diabetic)
insulin resistance (75%) among HS patients, but no validated clinical outcome
measure was used. However, the important additional benefit of metformin in
reducing insulin resistance in these patients was not assessed. If proven
effective in a prospective RCT, metformin could be the first treatment for
moderate HS which also reduces one of the most common comorbidities in this
population: insulin resistance.
Study objective
The primary objective of this study is to determine the clinical efficacy of
doxycycline and metformin compared with the standard treatment with doxycycline
alone after 24 weeks of treatment.
Study design
A 24-week, two arm, multicentre, double-blind, randomised controlled trial with
an add-on design in patients with mild to moderate hidradenitis suppurativa.
Intervention
Group A will receive doxycycline 100mg once a day for the duration of 24 weeks.
Group B will receive a combination of doxycycline 100mg once a day plus
metformin for the duration of the study. Metformin will be up-titrated from a
starting dose of 500mg a day in the first week, through 1000mg a day in week 2,
to a maximum of 1500mg a day from week 3 onwards. Group A will additionally be
given a placebo in the same dosing regimen as metformin to ensure blinding
between groups.
Study burden and risks
Patients will visit the hospital every 6 weeks for a duration of 24 weeks.
Venapuncture will be performed at every visit requiring patients to be fasting
for at least 6 hours. In addition patients will fill out questionnaires at
every visit. Doxycycline is currently a first line treatment for HS with known
efficacy. It is well tolerated and has an acceptable side-effect profile,
mainly comprised of gastro-intestinal side effects, increased sensitivity to
sunlight, and vaginal candidiasis among women. Metformin has shown promise as a
treatment for HS with the most common side effect being transient
gastro-intestinal complaints at the start of treatment. To reduce the
gastro-intestinal symptoms we will up-titrate the dose of metformin slowly over
the course of 3 weeks.
dr. Molewaterplein 40 Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
dr. Molewaterplein 40 Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
• Age >=18 years at baseline
• A diagnosis of HS for at least 1 year prior to baseline
• mild to moderately active disease defined by a HS Physician Global Assessment
(HS-PGA)
score of 2-3 and the Refined Hurley classification of mild to moderate
at baseline
• Indication for systemic therapy; i.e. uncontrolled disease under conventional
topical therapy.
• Able and willing to give written informed consent and to comply with the
study requirements.
Exclusion criteria
• Pregnant and lactating women
• Previously diagnosed diabetes mellitus and receiving active treatment
• Use of oral antibiotics within 14 days prior to baseline
• Use of immunosuppressing/modulating therapies within 28 days prior to baseline
• A known allergy to metformin or doxycycline or any of the ingredients
metformin or doxycycline
• Contraindications for the use of either metformin (e.g. acute metabolic
acidosis, or severe
kidney failure with a creatinine clearance < 30 ml/min) or doxycycline
(severe liver function
disorders)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005271-12-NL |
| CCMO | NL75745.078.20 |
| Other | NL9050 |