**Background:** Severe acute malnutrition (SAM) remains a major cause of morbidity and mortality in children under five in low- and middle-income countries, including Pakistan. Community-based management of SAM (CMAM) using ready-to-use therapeutic food (RUTF) is the standard of care, but the World Health Organization has called for complementary therapies to enhance recovery. Prebiotics such as galacto-oligosaccharides (GOS) may improve gut microbiota, reduce diarrhea, and enhance nutrient absorption. No prior randomized controlled trial had evaluated prebiotic supplementation in children with SAM in Pakistan.
**Methods:** A double-blind, parallel-treatment, randomized placebo-controlled trial was conducted at an outpatient therapeutic programme (OTP) centre in Dera Ghazi Khan, southern Punjab, Pakistan, from November 2020 to September 2021, with follow-up completed in December 2021. Children aged 6–59 months with uncomplicated SAM (MUAC <11.5 cm or weight-for-height z-score ≤−3, and no complications such as severe edema, high fever, hypoglycemia, or severe dehydration) were eligible. A total of 256 children were screened; 213 were enrolled and randomized 1:1 to receive either standard RUTF plus 4 g/day of GOS (Vivinal GOS powder, degree of polymerization 2–10, from Friesland Campina, Netherlands) or standard RUTF plus 4 g/day of starch placebo, for 8 weeks. The sample size was calculated as 79 per arm to detect a 16% absolute increase (from 76% to 92%) in the proportion gaining >15% baseline weight at 60 days (80% power, α=0.05), inflated to 97 per arm to account for 25% attrition. Final analysis included 204 children (102 per arm) after exclusions for consent withdrawal and loss to follow-up. Random allocation was generated in Excel with no blocking or stratification; sachets were identical in appearance. Staff, parents, and outcome assessors were blinded. Primary outcome was proportion gaining >15% baseline weight at 2 months. Secondary outcomes included mean weight, MUAC, hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), platelets, and serum albumin at 2 months. Safety endpoints were mortality and severe adverse events. Blood samples (2–3 mL) were analyzed using Sysmex XN 1000 (Japan) for complete blood count and Alinity Ci series (Abbot, IL, USA) for albumin. Statistical analysis used paired and independent t-tests in SPSS v25, with p<0.05 considered significant.
**Key Results:** Baseline characteristics were similar between groups. The majority of children were male (52.9%), aged ≤12 months (51.0%), Punjabi (60.3%), and resided in rural areas (63.7%). In the treatment group, paired t-tests showed significant increases from pre- to post-intervention for weight (mean difference −0.78 kg, p<0.001), MUAC (−0.71 cm, p<0.001), Hb (−0.80 g/dL, p<0.001), MCV (−3.22 fL, p<0.001), MCH (−1.99 pg, p<0.001), and albumin (−0.33 g/dL, p<0.001). HCT and platelet changes were not significant within the treatment group. Between-group comparisons at 2 months showed significantly greater improvements in the prebiotic group versus placebo for: post-weight (6.53 vs 5.89 kg, p=0.005), post-MUAC (10.80 vs 10.16 cm, p=0.001), post-Hb (10.57 vs 9.32 g/dL, p<0.001), post-HCT (46.53 vs 28.56%, p=0.006), post-platelets (271,500 vs 296,230/μL, p=0.031), post-MCV (74.35 vs 71.31 fL, p<0.001), post-MCH (25.31 vs 23.38 pg, p<0.001), and post-albumin (3.98 vs 3.77 g/dL, p=0.009). The treatment group gained approximately 20% of baseline weight (from 5.44 to 6.53 kg) versus 8.5% in controls (from 5.43 to 5.89 kg). No adverse events were reported in either arm.
**Clinical Implications:** This study provides the first RCT evidence from Pakistan that adding 4 g/day of GOS prebiotic to standard RUTF significantly improves weight gain, mid-upper-arm circumference, and multiple hematological and nutritional parameters in children with uncomplicated SAM over 8 weeks, with no safety concerns. The intervention appears safe and effective in a resource-limited setting with high poverty and poor sanitation. Limitations include a single-district setting (limiting generalizability), short follow-up (8 weeks), and lack of long-term sustainability data. Further multicenter trials with longer follow-up are needed to confirm these findings and assess durability of benefits.