Trial Information

Phase 2 Double-blind, Randomized, Placebo Controlled Clinical Trial for the Prevention of Oral Mucositis Using Sub-microbial Doses of Doxycycline Hyclate in Patients With Acute Leukemia Receiving Induction Chemotherapy

Background. Mucositis is a complication of chemotherapy with no effective treatment.

Aim.To evaluate the efficacy of sub-microbial doses of doxycycline hyclate in preventing the
development of oral mucositis in patients with acute leukemia (AL) treated with induction
chemotherapy.

Hypothesis. Doxycycline hyclate administration in sub-microbial dosage will reduce the
incidence of oral mucositis in patients with AL who receive induction chemotherapy.

Methods. Double-blind, randomized, placebo-controlled clinical trial. At the Cancer National
Institute (INCan), adult patients (> 18 years of age) with acute leukemia of recent
diagnosis, scheduled to receive induction chemotherapy will be enrolled in the study.
Written informed consent from the patients will be obtained preceding inclusion in the
study.

Stratification according to the type of acute leukemia (myeloblastic and lymphoblastic) will
be done. Random number tables will be used with balance for every four subjects; coded boxes
will be utilized to preserve double blinding. Patients will be randomly assigned to receive
either a sub-microbial dose of doxycycline hyclate or placebo (50 mg per day), immediately
before the initiation of induction chemotherapy and daily during the following 21 days after
chemotherapy.

At baseline and 3-times per week, during 21-days, patients will have an oral examination
performed using the Oral Mucositis Assessment Scale (OMAS). Also oral pain and difficulty to
swallow will be recorded using a visual analogue scale. Also in each visit, salivary flow
measurements (Schirmer's test modified version) will be done.

The OMAS system is a validated index that evaluates the severity of oral mucositis by
measuring the degree of ulceration/pseudomembrane and erythema in nine sites of the oral
mucosa (upper and lower lip, right and left inner cheek, right and left ventral and lateral
tongue, floor of the mouth, soft palate/fauces and hard palate). At each site, erythema is
evaluated using a 3-point scale (0=none, 1=mild/moderate, 2=severe), and
ulceration/pseudomembrane formation is evaluated using a 4-point scale (0=none, 1=cumulative
surface area <1 cm2, 2=cumulative surface area 1-3 cm2, 3=cumulative surface area >3 cm2).
The value of OMAS will be obtained by summing the erythema and ulceration/pseudomembrane
sub-scores at each site and then averaging these scores across the affected sites.

In order to rule out oral candidosis (OC), definitive diagnosis of OC requires the
identification of pseudohyphae in exfoliative cytology samples stained with periodic acid
Schiff. Likewise, the clinical diagnosis of herpes simplex virus (HSV) induced oral lesions
will be confirmed by the virus-infected cells demonstrated in cytologic smears stained with
Papanicolaou, and/or a clinical response to systemic antiviral therapy with acyclovir.

A sample size of 164 subjects has been calculated, 74 subjects in each arm of the study.
This estimate is based in the incidence of OM that is higher than 40% in patients with AL,
and considering its reduction to half (20%), assuming an alpha value of 0.05 (one-sided) and
a minimum statistical power of 0.80.

The efficacy primary end point of this study will be the proportion of patients treated with
doxycycline or placebo without oral lesions associated with OM, in the 21 days of follow-up.
Efficacy will be evaluated if the proportion of complete response (CR) is significantly
higher than the proportion of events in the placebo group. Additional secondary endpoints
will be the partial resolution of the oral lesions, the incidence of infections and the
mortality in the study groups during the 21 days of follow-up.

Statistical analysis. Results will be analysed by using Chi-squared test and
Wilcoxon-Mann-Whitney rank sum test.