Double-blind-randomized,Placebo Controlled Trial for Chemotherapy-associated Oral Mucositis Using Doxycycline Hyclate

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.

At baseline and 3-times per week, during 21-days, patients will have an oral examination performed using the Oral Mucositis Assessment Scale (OMAS), oral pain, difficulty to swallow, and salivary flow measurements will be recorded.

A sample size of 164 subjects has been calculated, 74 subjects in each arm of the study. The primary end point of this study to evaluate the efficacy will be the proportion of patients treated with doxycycline or placebo without oral lesions associated with OM, during 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. Results will be analyzed by using Chi-squared test and Wilcoxon-Mann-Whitney rank sum test.

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.

Inclusion Criteria:

• Adult patients (> 18 years of age) with acute leukemia of recent diagnosis,scheduled to receive induction chemotherapy.
• Capacity to give written informed consent.
• Ability to attend the follow-up visits.

Exclusion Criteria:

• Patients with allergy or intolerance to tetracyclines
• Patients with acute or chronic renal insufficiency (basal blood creatinine >1.9 mg/dl)
• Patients with the contraindication for the oral administration of drugs.
• Patients with active septic processes or considered resolved in less than 7 days before the start of chemotherapy.
• Patients who required tetracycline administration in the 28 days previous to randomization.
• Adult patients with acute leukemia schedule to undergo stem-cell transplantation in the following two weeks.
• Adult patients with hematological cancer with previous radiotherapy that may affect the salivary glands.
• Inability to authorize a written informed consent.

Exclusion criteria

• Patients who start chemotherapy before 12 hours of the assigned treatment.
• Patients who have received less than 10 doses (5 days) of the assigned treatment.
• Requirement to receive ergot derivates.
• Patients who require the administration of acitretin/isotretinoin/tretinoin
• Patients that receive photosensitive drugs during the study period (hydroxyquinone/retinoids or methoxsalen)